Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CN(C=O)C>[CH2:24]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:15][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 313.8 %

Procedure:
Potassium carbonate (24.8 g, 180 mmol) was added to a solution of 4-hydroxybenzaldehyde (3.66 g, 30 mmol) in DMF (90 mL) at room temperature. After the mixture was stirred at 60° C. for 1 h, 1-bromooctane (8.7 mL, 36 mmol) was added slowly. The reaction mixture was stirred overnight at 80° C. under N2, cooled to room temperature, and poured over 200 mL of icy water. The mixture was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo to give a yellow oil (13.67 g). 1H NMR (400 MHz, CDCl3, δ): 9.88 (s, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 4.06 (t, J=6.6 Hz, 2H), 1.83-1.76 (m, 2H), 1.62-1.23 (m, 18H), 0.90 (t, J=8.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:13][C:14](=O)[CH3:15])[N:7]=1)[CH3:2].Cl.[Cl:19][C:20]1[C:21]([F:28])=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:23]3[C:22](=[C:21]([F:28])[C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:14]=2[CH3:15])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(SCC(C)=O)n1
Reactant: NNc1cccc(Cl)c1F
Agent: Cl
Product: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [6-(2-oxo-propylsulfanyl)-pyridin-2-yl]-acetic acid ethyl ester and 3-chloro-2-fluorophenylhydrazine hydrochloride.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[F:9][C:10]1[CH:22]=[CH:21][C:13]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1.[O-]CC.[Na+]>C(O)(=O)C>[C:1]([CH:3]([CH:14]([C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:22][CH:21]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C=Cc1ccc(F)cc1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CC(c1ccc(F)cc1)C(C#N)C(=O)OCC
Temperature: 5 °C
Yield: 74.9 %

Procedure:
A mixture of ethyl cyanoacetate (13.56 g) and ethyl 4-fluorocinnamate (19.4 g) was added to a solution of sodium ethoxide (2.3 g sodium in 50 ml ethanol) at 60° C. over 2-3 minutes and the mixture heated under reflux for 1 hour then cooled to 5° C. Glacial acetic acid (6 ml) was added slowly to the reaction mixture at below 5° C. The bulk of the ethanol was removed by distillation at reduced pressure the residue diluted with water (40 ml), extracted with toluene (3×30 ml), and the combined organic phases dried over anhydrous magnesium sulphate. The solution was filtered, evaporated to an oil (28.6 g), and distilled at 166-180° C. at 3.5 mbar to produce diethyl 2-cyano-3-(4-fluorophenyl)-glutarate (23 g, 74% yield, 98% purity).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10]Br)=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22](=[N:30][OH:31])[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>CN(C)C=O>[F:3][C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][O:31][N:30]=[C:22]([C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[Cl:14])[CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:6][CH:5]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: ON=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(OCCON=C(Cc2cccnc2)c2ccc(Cl)cc2Cl)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
0.55 g of sodium hydride dispersion (50% in oil) and then 2.20 g of 2-(4-fluorophenoxy)ethyl bromide are added with stirring to a solution of 2.81 g of 2',4'-dichloro-2-(3-pyridyl)acetophenone oxime in 20 ml of dimethylformamide. The reaction mixture is heated to 100° C. and stirred at this temperature for 1 hour. It is then cooled to room temperature and poured onto ice. The aqueous mixture is extracted with methylene chloride, and the organic phase is washed twice with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After chromatography on silica gel using n-hexane/ethyl acetate (7:3) as the eluent, 2',4'-dichloro-2-(3-pyridyl)acetophenone O-[2-(4-fluorophenoxy)ethyl]oxime is obtained as an E/Z isomer mixture in the form of a slightly yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[N:21]=[C:20]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:19]=[CH:18][N:17]=1
Reactant: OB(O)c1cccs1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1nccc(-c2cccs2)n1
Temperature: 25 °C

Procedure:
A solution of 2.0 g (15.6 mmol) of 2-thiopheneboronic acid in 80 mL of a 5% (w/v) Na2CO3 aqueous solution was added drop wise to a refluxing solution of 4.7 g (31 mmol) of 2,4-dichloropyrimidine and 0.55 g (0.78 mmol) of bis(triphenylphosphine)palladium(II) chloride in 80 mL of MeCN. The reaction solution was heated at reflux for 6 h, then cooled to rt, the organic solvent removed in vacuo, and the resulting purple solid filtered and washed with water. The crude product was purified by flash chromatography eluting with a linear gradient of neat hexane to neat EtOAc to deliver the title compound. MS (M+H)+ 197.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[C:39]([NH:41][NH2:42])=[O:40])(=[O:13])=[O:12].C(N(C(C)C)C(C)C)C.[Br:52][CH2:53][CH2:54][CH2:55][C:56](Cl)=[O:57]>C1COCC1>[Br:52][CH2:53][CH2:54][CH2:55][C:56]([NH:42][NH:41][C:39]([C@@H:15]1[CH2:16][C@@H:17]([S:19][C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:18][N:14]1[S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12])=[O:40])=[O:57]
Reactant: O=C(Cl)CCCBr
Reactant: NNC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCCBr)NNC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
(step 27) To 150 mg (0.25 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid hydrazide in 65 ml THF were added 52 μl (0.3 mmol, 1.2 eq) iPr2EtN and 29 μl (0.25 mmol) 4-bromobutyryl chloride at 0° C. The solution was stirred at RT for 2 h, the solution was concentrated and redissolved in ethyl acetate/H2O. The inorganic phase was extracted with ethyl acetate and, the organic phase was washed with brine and dried over Na2SO4. Column chromatography with ethyl acetate:hexane 1:1 yields 170 mg (92%) (2S,4R)-1(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid N′-(4-bromo-butyryl)-hydrazide which was dissolved in 120 ml DMF and treated with 17 mg (0.38 mmol, 55% in mineral oil). NaH and the solution stirred for 2 h, was concentrated and dissolved in ethyl acetate/H2O. The inorganic phase was extracted with ethyl acetate, the organic phase washed with brine and dried over Na2SO4. The crude product was purified by column chromatography yielding 75 mg (45%) (2S,4R)-4-tritylsulfanyl -1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid (2-oxo-pyrrolidin-1-yl)-amide as white foam and 40 mg (25%) (2S,4R)-1-[4-tritylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-tetrahydro-pyridazin-3-one as white foam. The two compounds were treated separately in TFA (2 ml/mmol tritylsulfanyl) with 10 eq triethylsilane at 0° C. to RT, until no educt could be detected, to yield (2S,4R)-4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid (2-oxo-pyrrolidin-1-yl)-amide as white foam, MS: 420 (MH+) and (2S,4R)-1-[4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-tetrahydro-pyridazin-3-one as white foam, MS: 420 (MH+), respectively.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[O:18][C:19]4[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:20]=4[CH:21]=3)[CH2:14][CH2:15][C:9]=2[CH:8]=1>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[O:18][C:19]4[CH:25]=[CH:24][C:23]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:22][C:20]=4[CH:21]=3)[CH2:14][CH2:15][C:9]=2[CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)CCN(Cc1cc3cc(N)ccc3o1)CC2
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN(Cc1cc3cc(NS(C)(=O)=O)ccc3o1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl cloride (0.28 ml) was added dropwise to a solution of 7-amino-3-(5-aminobenzofur-2-ylmethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine (0.56 g) in pyridine (40 ml) cooled to 0° and the mixture was then stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue taken up in methylene chloride, washed three times with aqueous sodium bicarbonate and three times with brine. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo to give an oil which was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 4%). The product-containing fractions were combined and evaporated to give the title compound as a foam, yield 0.56 g.
Reaction SMILES: O[C:2]([CH3:11])([CH3:10])[CH2:3][C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1.C(N(S(F)(F)[F:18])CC)C.C([O-])(O)=O.[Na+]>ClCCl>[F:18][C:2]([CH3:11])([CH3:10])[CH2:3][C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1
Reactant: CC(C)(O)C[C@H]1COC(=O)N1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)C[C@H]1COC(=O)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A dichloromethane solution (100 mL) of the alcohol (47.8 g) from Step 3 was added to a −70° C. solution of (diethylamino)sulfur trifluoride (48.5 g) in dichloromethane (500 mL). The mixture was warmed to room temperature and stirred for 1 hour. The mixture was then carefully added to a 0° C. mixture of saturated aqueous NaHCO3 (800 mL). The organic layer was separated and washed with saturated aqueous NaHCO3. The aqueous was further extracted with dichloromethane (100 mL) and the combined dichloromethane layers were dried and concentrated. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes (1:5) followed by ethyl acetate to yield (4S)-4-(2-fluoro-2-methylpropyl)-1,3-oxazolidin-2-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[Li]CCCC.CN([CH:18]=[O:19])C>O1CCCC1>[Br:8][C:4]1[C:3]([CH3:9])=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:18]=[O:19]
Reactant: Cc1c(Br)cccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1C=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 100.5 %

Procedure:
To a solution of 1,3-dibromo-2-methylbenzene (3 g, 12.00 mmol) in Tetrahydrofuran (THF) (100 mL) stirred under nitrogen at −78° C. was added BuLi (9.00 mL, 14.40 mmol) dropwise. The reaction mixture was stirred at −78° C. for 20 min. DMF (1.115 mL, 14.40 mmol) was added dropwise. The reaction mixture was continuously stirred for 2 hours. The reaction was quenched with sat. aq. ammonia chloride solution. The aqueous layers were separated and extracted by EA for 3 times. The combined organic layers were washed by brine, dried over anhydrous sodium sulfate. The dried solution was concentrated in vacuo to afford 3-bromo-2-methylbenzaldehyde (D93) (2.4 g), which was used for the next step without further purification. MS (ES): C8H7BrO requires 197.9. found 199 (M+H+)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]([N+:13]([O-:15])=[O:14])([CH3:12])[CH2:10][OH:11].C(N(CC)CC)C>ClCCl>[CH3:8][C:9]([N+:13]([O-:15])=[O:14])([CH3:12])[CH2:10][O:11][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(CO)[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(C)(C)[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 92.2 %

Procedure:
Acetic anhydride (0.34 ml, 3.60 mmol) was added to a solution of 2-methyl-2-nitro-1-propanol (375.4 mg, 3.15 mmol) and triethylamine (0.80 ml, 5.74 mmol) in dichloromethane (5 ml) and stirred for 2.5 hours. The mixture was concentrated and purified by silica gel chromatography (hexane/ether=3/1) to give the title compound (467.8 mg; 92%).
Reaction SMILES: O[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:15][CH3:16].C(Cl)(=O)C([Cl:20])=O.O>CN(C=O)C>[Cl:20][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OC)c(Cl)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
A solution of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2) (4.4 g, 19 mmol) in DMF (30 mL) at 0° C. was treated with oxalyl chloride (5.09 mL, 58.1 mmol) dropwise. The mixture was then stirred at 80° C. for 3 h under a CaCl2 drying tube. The mixture was allowed to cool to RT, poured in to iced water (100 mL) and stirred for 15 min. The precipitate was collected by filtration and washed with water and MeOH to afford methyl 4-chloro-3-methoxy-5-nitrobenzoate (3) (3.2 g, 65% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ: 8.04 (1H, d), 7.77 (1H, d), 4.04 (3H, s), 3.97 (3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([CH:16]=O)=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.Cl.[NH2:19]O>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:19])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: NO
Reactant: O=Cc1cnn2c(-c3cccnc3)ccnc12
Agent: Cl
Solvent: CCO
Product: N#Cc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.01 mole of 7-(3-pyridyl)pyrazolo-[1,5-a]pyrimidine-3-carboxaldehyde and 0.011 mole of hydroxylamine hydrochloride in 25 ml. of ethanol is heated on a steam bath for 3 hours. The solvent is removed and to the residue is added 25 ml. of acetic anhydride. The mixture is heated at reflux temperature for 6 hours and the solvent is removed in vacuo. The residue is partitioned between dichloromethane and sodium bicarbonate solution and the organic layer is separated, dried over magnesium sulfate, and the solvent removed to give the product of the example, m.p. 258°-260° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:43][CH2:42][N:41]([CH:44]6[CH2:47][O:46][CH2:45]6)[CH2:40][CH2:39]5)=[CH:34][N:33]=4)[C:28](=[O:48])[N:27]([CH3:49])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:39][CH2:40][N:41]([CH:44]6[CH2:47][O:46][CH2:45]6)[CH2:42][CH2:43]5)=[CH:34][N:33]=4)[C:28](=[O:48])[N:27]([CH3:49])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
A mixture of 103c (120 mg, 0.18 mmol), NaBH4 (21 mg, 0.54), and CH3OH (10 mL) was stirred at 25° C. for 1 h. It was then concentrated under reduced pressure and water (10 mL) was added. The resulting mixture was extracted with CH2Cl2 (10 mL×2). The combined CH2Cl2 extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 103 (45 mg, 38%). LCMS: [M+H]+ 667. 1H NMR (500 MHz, CDCl3) δ 8.66-8.68 (m, 2H), 8.35 (s, 1H), 7.96 (d, J=3.0, 1H), 7.81 (s, 1H), 7.65 (d, J=2.5, 1H), 7.55-7.59 (m, 3H), 6.83 (d, J=8.5, 1H), 4.71-4.74 (m, 4H), 4.51-4.52 (m, 2H), 4.07-4.08 (m, 1H), 3.73 (s, 3H), 3.56 (s, 1H), 3.20-3.22 (m, 4H), 2.56-2.58 (m, 4H), 1.59 (s, 9H)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1[N:7]([CH2:15][CH2:16][C:17]#[C:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([N:25]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([C:18]#[C:17][CH2:16][CH2:15][N:7]2[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=[N:6]2)[N:24]=1)[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(C#CCCn2nc3ccccc3n2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1cccc(C#CCCn2nc3ccccc3n2)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A solution of methanesulfonyl chloride (98 mg, 0.85 mmol) in DCM was added to a solution of 6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-ylamine (100 mg, 0.38 mmol, Example 169(A)) and Et3N (0.12 mL, 0.85 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then the solvent was evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 140 mg (0.33 mmol, 88%) of N-methylsulfonyl-N-[6-(4-benzo[d][1,2,3]triazol-2-yl-but-1-ynyl)-pyridin-2-yl]-methylsulfonamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]CO)[CH2:14][CH2:13]3)[C:9]3[CH:22]=[C:23]([CH:26]([CH3:28])[CH3:27])[CH:24]=[CH:25][C:8]=3[S:7][C:6]=2[CH:29]=1.[C:30]([O:33]C(=O)C)(=[O:32])[CH3:31]>C(Cl)(Cl)Cl>[C:30]([O:33][CH2:19][CH2:18][N:15]1[CH2:14][CH2:13][N:12]([CH:10]2[C:9]3[CH:22]=[C:23]([CH:26]([CH3:27])[CH3:28])[CH:24]=[CH:25][C:8]=3[S:7][C:6]3[CH:29]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH2:11]2)[CH2:17][CH2:16]1)(=[O:32])[CH3:31]
Reactant: CC(C)c1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccc(F)cc1S2
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCN1CCN(C2Cc3ccc(F)cc3Sc3ccc(C(C)C)cc32)CC1
Reaction time: 8 h

Procedure:
A solution of 1.0 g of 3-fluoro-10-[4-(2-hydroxyethyl)piperazino]-8-isopropyl-10,11-dihydrodibenzo(b,f)thiepin base (Example 3) in 5 ml chloroform was treated with 0.5 g acetic anhydride and the mixture allowed to stand overnight at room temperature. It was then diluted with 20 ml of chloroform, washed with water and with ice-cold sodium hydroxide solution, dried with potassium carbonate, and the chloroform evaporated under reduced pressure. The remaining oil (1.1 g, 100%) was dissolved in 3.5 ml of acetone and the solution neutralized under heating with 0.6 g maleic acid. On cooling, 1.3 g (77%) of dimaleate crystallized which was then recrystallized from acetone and melted at 153°-155.5° C.; it was identical with the product obtained by a different way according to Example 14.
Reaction SMILES: [OH:1][C:2]1([CH3:18])[CH2:7][CH2:6][C@@H:5]([NH:8]C(=O)OC(C)(C)C)[CH2:4][C:3]1([CH3:17])[CH3:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:5]1[CH2:6][CH2:7][C:2]([CH3:18])([OH:1])[C:3]([CH3:17])([CH3:16])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC(C)(O)C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C[C@H](N)CCC1(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 133.1 %

Procedure:
To a solution of tert-butyl ((1R)-4-hydroxy-3,3,4-trimethylcyclohexyl)carbamate (520 mg, 2.15 mmol) in DCM (6.00 mL) was added TFA (3.00 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 h. The reaction was concentrated in vacuo to give a crude product (450 mg, crude), which was used directly in the next step without further purification. MS (ESI) m/z 158.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[Cl:28][C:29]1[S:30][C:31]([Cl:38])=[CH:32][C:33]=1[S:34](Cl)(=[O:36])=[O:35].N1C=CC=CC=1>O1CCCC1>[Cl:28][C:29]1[S:30][C:31]([Cl:38])=[CH:32][C:33]=1[S:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1)(=[O:36])=[O:35]
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCOc1ccc(NS(=O)(=O)c2cc(Cl)sc2Cl)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
150 mg (0.408 mmol) of the compound from example 44A are reacted with 308 mg (1.224 mmol) of 2,5-dichlorothiophene-3-sulfonyl chloride and 0.33 ml (4.08 mmol) of pyridine in tetrahydrofuran for 4 hours.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([O:9][CH:10](OCC)[CH2:11][NH2:12])[CH3:8].C(S(O)(=O)=O)(F)(F)F.[OH-].[K+]>O1CCOCC1>[Br:1][C:2]1[S:3][CH:4]=[C:5]2[C:6]=1[CH2:8][CH2:7][O:9][CH:10]2[CH2:11][NH2:12]
Reactant: CCOC(CN)OCC
Reactant: Brc1cccs1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NCC1OCCc2c1csc2Br
Temperature: 22 °C
Reaction time: 2 h

Procedure:
Bromothiophene (0.31 g, 1.5 mmol) and aminoacetaldehyde diethyl acetal (0.3 g, 2.25 mmol) were combined with 1,4-dioxane (2 mL). CF3SO3H (0.45 g, 3.0 mmol) was added and the reaction mixture was stirred at 22° C. for 2 hr at which time the mixture was made basic with 10% KOH (aq.) and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent removed in vacuo to afford the crude amine product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.I[C:18]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C@@:26]([CH3:41])([S:37]([CH3:40])(=[O:39])=[O:38])[C:27]([NH:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)=[O:28])[C:20](=[O:42])[CH:19]=1.O>O1CCOCC1.[Pd]>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C@@:26]([CH3:41])([S:37]([CH3:40])(=[O:39])=[O:38])[C:27]([NH:29][O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)=[O:28])[C:20](=[O:42])[CH:19]=2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(-c2ccc(F)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 80 °C

Procedure:
Pd EnCat™ (200 mg, 0.06 mmol) was added to a mixture of potassium carbonate (250 mg, 1.81 mmol), (4-fluorophenyl)boronic acid (84 mg, 0.602 mmol), and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, which may be produced as in Preparation 2 B, (300 mg, 0.602 mmol) in dioxane:water (5.5 mL, 10:1mixture) in a 25 mL round bottom flask. The flask was heated overnight at 80° C. The reaction was cooled to ambient temperature and filtered through celite and washed with ethyl acetate (20 mL). The crude material was concentrated, and purified by chromatography on silica gel (gradient: 100:0 dichloromethane:methanol to 95:5 dichloromethane:methanol) to provide title compound as a viscous, foamy oil. Yield: 257 mg, 91.5%. MS (APCI) m/z 467.6 (M+H) 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54-1.65 (m, 3H) 1.68 (d, J=2.34 Hz, 3 H) 1.71-1.99 (m, 3 H) 2.32-2.44 (m, 1 H) 2.44-2.57 (m, 1 H) 3.18 (d, J=2.93 Hz, 3 H) 3.54-3.66 (m, 1 H) 3.97-4.10 (m, 1 H) 4.11-4.25 (m, 1 H) 4.25-4.38 (m, 1 H) 5.16 (d, J=15.81 Hz, 1 H) 6.48 (dd, J=6.93, 1.27 Hz, 1 H) 6.76 (s, 1 H) 7.12 (t, J=8.59 Hz, 2 H) 7.39 (d, J=7.02 Hz, 1 H) 7.47-7.57 (m, 2 H) 12.15 (d, J=7.42 Hz, 1 H)