Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:13][CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)=[O:18]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NCCC#Cc1cccc(CF)n1
Product: O=C(NCCC#Cc1cccc(CF)n1)c1ccccc1Cl
Yield: 19.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 184, from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-amine (39 mg, 0.22 mmol, Example 189(D)) and 2-chlorobenzoyl chloride (50 mg, 0.28 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 13.5 mg (43 μmol, 19%) of 2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide as a colorless oil.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:7]2[C:8]([NH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]=1[CH3:13])=O.S(Cl)([Cl:16])=O>CN(C=O)C>[Cl:16][C:8]1[C:7]2[C:3]([CH2:2][CH3:1])=[C:4]([CH3:13])[S:5][C:6]=2[N:12]=[CH:11][N:10]=1
Reactant: CCc1c(C)sc2nc[nH]c(=O)c12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1c(C)sc2ncnc(Cl)c12
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A mixture of 5-ethyl-6-methyl-3-hydrothiopheno[2,3-d]pyrimidin-4-one (0.5 g), thionyl chloride (5 mL) and catalytic amount of DMF (0.2 mL) was refluxed for 1 h. Solvents were removed under vacuum and the mixture was diluted with ice cold water and stirred for 10 min. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was triturated with hexane to give the product as a dark brown color solid (400 mg, 73%), mp 52-56° C. 1H NMR (400 MHz, CDCl3): δ 8.73 (1H, s), 3.05 (2H, q, J=7.5 Hz), 2.55 (3H, s), 1.24 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:16]Br>C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc(CBr)cc1
Reaction time: 0.01 h
Yield: 60 %

Procedure:
4-Methylbenzophenone, 750 g (3.82 moles), was added to a 5 liter Morton flask equipped with an overhead stirrer and dissolved in 2850 ml of benzene. The solution was then heated to reflux, followed by the dropwise addition of 610 g (3.82 moles) of bromine in 330 ml of benzene. The addition rate was approximately 1.5 ml/min and the flask was illuminated with a 90 watt (90 joule/sec) halogen spotlight to initiate the reaction. A timer was used with the lamp to provide a 10% duty cycle (on 5 seconds, off 40 seconds), followed in one hour by a 20% duty cycle (on 10 seconds, off 40 seconds). At the end of the addition, the product was analyzed by gas chromatography and was found to contain 71% of the desired Compound VI, 8% of the dibromo product, and 20% unreacted 4-methylbenzophenone. After cooling, the reaction mixture was washed with 10 g of sodium bisulfite in 100 ml of water, followed by washing with 3×200 ml of water. The product was dried over sodium sulfate and recrystallized twice from 1:3 toluene:hexane. After drying under vacuum, 635 g of Compound VI were isolated, providing a yield of 60% and having a melting point of 112-114° C. Analysis on an NMR spectrometer was consistent with the desired product: 1H NMR (CDCl3) aromatic protons 7.20-7.80 (m, 9H) and benzylic protons 4.48 (s, 2H). The final compound was stored for use in the preparation of a photoactivatable chain transfer agent as described in Example 7.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([O:12][CH3:13])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[F:9])#[CH:2].Br[C:16]1[N:17]=[C:18]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.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>[F:14][C:4]1[C:5]([O:12][CH3:13])=[CH:6][C:7]([O:10][CH3:11])=[C:8]([F:9])[C:3]=1[C:1]#[C:2][C:16]1[N:17]=[C:18]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=1
Reactant: C#Cc1c(F)c(OC)cc(OC)c1F
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Br)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OC)c(F)c(C#Cc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)c1F
Reaction time: 14 h
Yield: 62.6 %

Procedure:
To a stirred solution of 3-ethynyl-2,4-difluoro-1,5-dimethoxybenzene (340 mg, 1.72 mmol) and 2-bromo-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (696 mg, 2.06 mmol, from Example 1, Step 1) in N,N-dimethylformamide (4 mL), copper(I) iodide (26 mg, 0.14 mmol), bis(triphenylphosphine)palladium(II) chloride (60.0 mg, 0.0885 mmol) and triethylamine (0.36 mL, 2.6 mmol) were added sequentially at room temperature. After 14 hours, the reaction was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated. The residue was purified on silica gel (eluting with 0 to 50% ethyl acetate (EtOAc) in hexanes) to give the desired product (490 mg, 63%). LCMS calculated for C22H15F2N3O4S (M+H)+: m/z=456.1. Found: 456.1.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]([OH:8])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[CH:2]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>O1CCCC1>[CH2:27]=[CH:26][C:25]([O:8][C:4]1[CH:5]=[C:6]([Cl:7])[CH:1]=[CH:2][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])=[O:28]
Reactant: C=CC(=O)Cl
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Irgasan® DP300 5-chloro-2-(2,4-dichlorophenol)(triclosan), 23.5 g (0.081 mol) was dissolved in 300 ml of dry tetrahydrofuran in a 1-l jacketed kettle with agitator, addition funnel and reflux condenser. Then 10.6 ml of triethylamine was added to the solution with agitation. To the resulting solution was added dropwise 6.68 (0.0738 mol) g of acryloyl chloride. The reaction temperature was maintained at 20° C. with a circulating cooling bath. After the addition of acryloyl chloride was completed, the agitation and temperature conditions were maintained for 5 hours. Then the reaction product was kept overnight at room temperature, filtered to remove solid triethylamine hydrochloride and the filtrate rotovapped at room temperature under 100-110 mm Hg to concentrate the product. The remaining solution was dissolved in 100 ml heptane and washed with 5% Na2CO3 solution in Dl water until basic; then with Dl water until neutral. The heptane solution of the product was dried with MgSO4 in a refrigerator overnight, and filtered. The filtrate contained 25.3% triclosan acrylate as determined by bromination. FTIR spectrum confirmed the presence of the unsaturated ester of a phenol (1753 cm−1).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>ClCCl>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][CH:10]1[NH:9][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)Cl
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
200 ml of dichloromethane then 10 ml, i.e. 7.26 g (71.7 mmol) of triethylamine were added to 5 g (29.5 mmol) of 2-aminoindan hydrochloride. The mixture was stirred for 30 min, then 3.4 ml, i.e. 3.84 g (35.4 mmol) of ethyl chloroformate were added dropwise. The mixture was stirred for 30 min, then ice-water and an excess of 1N hydrochloric acid were added. The precipitate was filtered, washed, dried and purified by chromatography on a silica gel column, eluted with an 80:20 mixture of dichloromethane/ethyl acetate. 4.25 g of amorphous solid were isolated.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=3)[CH:19]=[CH:20][C:21]=2[CH:22]=[CH2:23])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].B12CC(CCC1)CC[CH2:36]2.[OH-:44].[Na+].OO>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=3)[CH:19]=[CH:20][C:21]=2[CH2:22][CH2:23][CH2:36][OH:44])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc(N(CC)CC)c(C(C)(C)C)c1
Reactant: C1CB2CCCC(C1)C2
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(CCCO)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
8 g of ethyl 3″-tert-butyl-4″-diethylamino-4′-vinyl[1,1′;3′,1″]terphenyl-4-carboxylate (17 mmol) are dissolved in 400 mL of THF with stirring and, under cold conditions (ice bath), 6.2 g of 9 borabicyclo[3.3.1]nonane (51 mmol) are added and the ice bath is removed to raise the temperature of the reaction medium to room temperature, at which point the reaction medium is stirred for 1 hour 30 minutes. The temperature of the reaction medium is again reduced to 0° C., 52.8 mL of NaOH (53 mmol) are added portionwise, and the medium is stirred for 10 minutes at 0° C.; 37.3 mL of H2O2 (426 mmol) are then added dropwise and the reaction medium is warmed to room temperature and then stirred for 2 hours 30 minutes. The reaction is stopped by adding 500 mL of ice-water and then extracted with 500 mL of ethyl acetate. The organic phases are washed with 1 L of water and then dried over magnesium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (eluent: 7/3 heptane/ethyl acetate). 6.4 g of ethyl 3″-tert-butyl-4″-diethylamino-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=75%).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1)([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36](C(=O)C2C=CC=CC=2)[CH:35]=1)(=O)C1C=CC=CC=1>>[NH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([CH2:33][N:6]2[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]2)=[CH:35]1
Reactant: O=C(OCc1cn(C(=O)c2ccccc2)c2ccccc12)c1ccccc1
Reactant: CCOC(=O)c1cc(C(C)C)n[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCOC(=O)c1cc(C(C)C)nn1Cc1c[nH]c2ccccc12
Reaction time: 0.75 h

Procedure:
To an oven dried flask cooled under argon equipped with a stir bar was added ethyl 3-isopropyl-1H-pyrazole-5-carboxylate (0.044 grams, 0.24 mmol, 0.1 in anhydrous 1,4 dioxane). While stirring at room temperature KHMDS (0.3 mL, 0.261 mmol, 0.87 M in toluene) was added. After stirring for 45 minutes, a solution of (1-benzoyl-1H-indol-3-yl)methyl benzoate (0.02 grams, 0.056 mmol, in 1.0 mL of anhydrous 1,4 dioxane) was added and the reaction mixture stirred over night. The next day, the reaction was quenched with 0.1M HCl and the organic material extracted with ethyl acetate. The aqueous solution was then salted out using sodium chloride and washed twice with ethyl acetate. The combined organic material was then dried with sodium sulfate, filtered, and concentrated. Purification using a Teledyne ISCO chromatography on silica gel (hexanes/ethyl acetate gradient) followed by a Teledyne ISCO chromatography using C18 reverse phase (water with 0.1% formic acid, acetonitrile gradient) afforded the desired compound. Yield, 63%. 1H NMR δ 8.29 (bs, 1H), 7.58 (d, 1H), 7.36 (d, 1H), 7.20 (t, 1H), 7.11 (t, 1H), 6.96 (s, 1H), 6.62 (s, 1H), 5.58 (s, 2H), 4.41 (q, 2H), 3.03 (m, 1H), 1.39 (t, 3H), 1.16 (d, 6H). Calculated mass for C18H21N3O2, 311.16. Observed 334.1 (M+1).
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[CH2:11][CH2:12][CH:13]=O.[Cl-].[CH2:16]([O:23][C:24]1[CH:49]=[CH:48][CH:47]=[CH:46][C:25]=1[CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH:13]=[CH:26][C:25]1[CH:46]=[CH:47][CH:48]=[CH:49][C:24]=1[O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CCCc1ccc2ccccc2c1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C(=Cc1ccccc1OCc1ccccc1)CCc1ccc2ccccc2c1
Yield: 82.7 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, 1.73 g of 3-(2-naphthyl)propanal prepared as described above, 4.65 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 2.15 g of 1,8 -diazabicyclo[5,4,0]undec-7-ene were reacted in 200 ml of acetonitrile. The reaction mixture was worked up and purified as described in the first part of Preparation 3, to obtain 2.83 g (yield 82%) of 4-(2-naphthyl)-1-(2-benzyloxyphenyl)-1-butene as a colorless oil.
Reaction SMILES: II.[C:3]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[CH2:4][C:5]([O-:7])=O.C(N(CC)C(C)C)(C)C.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5]([NH:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][C:27]([F:26])([F:36])[F:37])[CH:30]=1)=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: II
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)OCc1ccccc1)Nc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.4 %

Procedure:
Preparation I2, Step 1: A solution of mono-benzyl malonate (1.1 g, 5.6 mmol) in 3:1 CH2Cl2/DMF (28 mL) was treated sequentially with N,N-diisopropylethylamine (2.5 mL, 14.0 mmol), meta-trifluoromethoxy-phenylamine (0.75 mL, 5.6 mmol), and HATU (2.6 g, 6.7 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide N-(3-trifluoromethoxy-phenyl)-malonamic acid benzyl ester as an oil (1.65 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:35][C:36]([CH3:49])([CH3:48])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:35][C:36]([CH3:49])([CH3:48])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:23])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(N)CCCNC(=O)OC(C)(C)C
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCCNC(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) in 6 mL of DMF was added EDCI (123 mmol, 0.64 mmol), DMAP (110 mg, 0.90 mmol) and tert-butyl 4-amino-4-methylpentylcarbamate (139 mg, 0.64 mmol) in one portion at room temperature and the mixture stirred at room temperature for 16 hours. The reaction mixture was poured into 40 mL of water, filtered, the filter cake washed with petroleum ether then dried to give crude tert-butyl 4-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-4-methylpentylcarbamate (75 mg, 46%) as a yellow solid. MS: (M+H)+=510.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([CH2:11][C:12]([O:14]C)=O)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[NH3:16]>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([CH2:11][C:12]([NH2:16])=[O:14])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: N
Reactant: COC(=O)CS(=O)(=O)c1cncc(Br)c1
Solvent: CO
Product: NC(=O)CS(=O)(=O)c1cncc(Br)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(5-bromopyridin-3-ylsulfonyl)acetate (0.2 g, 0.67 mmol) was added 5% ammonia in methanol (10 mL). Upon completion of addition, the reaction mixture was stirred at 60° C. for 4 h. After this time, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was concentrated under reduced pressure to afford 2-(5-bromopyridin-3-ylsulfonyl)acetamide (0.2 g) as a white solid. LCMS Method W: retention time 0.92 min; [M−1]=277.0.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[NH2:9][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[N:4]=1
Reactant: Nc1nc(=O)[nH]cc1F
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Nc1nc(OS(=O)(=O)c2ccccc2)ncc1F
Yield: 28.1 %

Procedure:
To a suspension of 5-fluorocytosine (0.177 g, 1.4 mmol) in pyridine (5 mL) was added and benzene sulfonyl chloride (0.284 g, 1.6 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness and the crude material purified by reverse phase chromatography to yield the title compound (0.106 g, 29% yield) as a white solid: mp 145-146° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.05-8.00 (m, 3H), 7.9-7.75 (m, 3H), 7.70-7.63 (m, 2H); HPLC-MS (ESI) m/z 270 (M+H)+, 268 (M−H)−.
Reaction SMILES: [C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH:33][CH3:34])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:11]([C:35]([O:37]C)=[O:36])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O.CO.O1CCCC1>[C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH:33][CH3:34])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:11]([C:35]([OH:37])=[O:36])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)O)cc1
Yield: 95.3 %

Procedure:
The procedure of Example 42 was followed using the product from Example 41 (280 mg, 0.526 mmol), lithium hydroxide (55 mg, 1.32 mmol) in water (0.4 ml), methanol (1 ml) and tetrahydrofuran (1 ml) to give 260 mg (95%) of the product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41][NH:42][CH2:43]C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:41][N:42]([CH3:43])[CH2:9][CH2:8][N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11]
Reactant: CCNC
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CCN(C)C)c4)cc23)CC1
Yield: 40.3 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting [2-(dimethylamino)ethyl]methylamine (102 mg, 1.0 mmol) for N-methylethanamine to afford 26.0 mg of the title compound (40.3%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5](=[O:8])[C:4]([O:9]CC2C=CC=CC=2)=[C:3]1[CH3:17]>Br>[CH3:1][N:2]1[CH:7]=[CH:6][C:5](=[O:8])[C:4]([OH:9])=[C:3]1[CH3:17]
Reactant: Cc1c(OCc2ccccc2)c(=O)ccn1C
Agent: Br
Product: Cc1c(O)c(=O)ccn1C
Yield: 82.4 %

Procedure:
1,2-Dimethyl-3-benzyloxypyrid-4-one (2 g) is added to concentrated hydrobromic acid (10 ml) and heated in a steam bath for 30 minutes. The resulting mixture is then recrystallised from water to yield 1,2-dimethyl-3-hydroxypyrid-4-one (1 g), m.p. 230° C. (with decomposition); νmax (nujol) 1620, 3150 cm-1 ; δ(d6DMSO) 2.3(s, 3H), 3.8(s, 3H), 6.9(d, 1H), 7.8(d, 1H); M+ 139.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH2:6][NH:7][CH2:8][CH2:9][CH:10]=1.Cl.O.Cl[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15]>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:1][O:2]/[N:3]=[CH:4]/[C:5]1[CH2:6][N:7]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:8][CH2:9][CH:10]=1
Reactant: C=CCOC(=O)Cl
Reactant: CON=CC1=CCCNC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CCOC(=O)N1CCC=C(/C=N/OC)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,2,5,6-tetrahydropyridin-3-carboxaldehyde-O-methyloxime in 40 cm3 of benzene, 1.5 cm3 of triethylamine and 1.17 cm3 of 2-propenyl chloroformate are added. The mixture is agitated for 30 minutes at ambient temperature, then treated with 20 cm3 of 5% hydrochloric acid, then twice with 20 cm3 of water. The solvent is evaporated off, then the residue is distilled at 200° C. under 0.08 mbar. 2.25 g of the expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH:39]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:45][S:42]([CH:39]3[CH2:41][CH2:40]3)(=[O:44])=[O:43])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1ccc(Cl)c(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)O)cnn23)c1
Reactant: NS(=O)(=O)C1CC1
Product: Cc1ccc(Cl)c(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 48.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chloro-5-methylphenylamino)-6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.160 g, 0.282 mmol) obtained in Example 142, step 2 and cyclopropanesulfonamide (0.170 g, 1.41 mmol), the title compound (0.087 g, 48%) was obtained.
Reaction SMILES: [CH:1]([CH:3]([CH2:10][CH3:11])[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[O:2].[C:12](=[O:15])([O-])[O-].[K+].[K+].[CH3:18]O>S(=O)(=O)(O)O>[CH3:18][O:2][CH:1]([O:15][CH3:12])[CH:3]([CH2:10][CH3:11])[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CCC(C=O)CCC(=O)OC
Reactant: CO
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCC(CCC(=O)OC)C(OC)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution containing anhydrous methanol (70 ml) and concentrated sulfuric acid (3 drops) was added methyl 4-formylhexanoate (10.2 g, 64.5 mmol). The solution was stirred at room temperature for 24 hours then solid potassium carbonate was added to neutralize the acid. Most of the solvent was evaporated under vacuum, then water (100 ml) was added and the solution extracted twice with hexane (50 ml) then twice with ether. The organic phases were combined and dried over anhydrous magnesium sulfate.