Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([NH:15][CH:16]([CH:24]([OH:35])[C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)C1C=CC=CC=1>O1CCCC1>[NH2:15][CH:16]([CH:24]([OH:35])[C:25]([F:33])([F:34])[C:26]([F:31])([F:32])[C:27]([F:28])([F:29])[F:30])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(F)(F)C(F)(F)C(F)(F)F)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(Cc1ccccc1)C(O)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Lithium aluminum hydride (118 mg) is added to a solution of (2RS,3RS)-2-benzoylamino-4,4,5,5,6,6,6-heptafluoro-3-hydroxy-1-phenylhexane (1.10 g, Reference compound No. 31-2) in anhydrous tetrahydrofuran (20 ml), and the mixture is stirred for three days. The reaction mixture is filtered through Celite to remove impurities. The filtrate is concentrated under reduced pressure, diethyl ether is added to the resulting residue, and the whole is extracted with 0.1 N hydrochloric acid. Sodium hydrogencarbonate is added to the extract to basify the system, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure to give the titled reference compound (164 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[C:9]([CH3:18])=[N:10][CH:11]=[C:12]([CH:16]=O)[C:13]=1[CH2:14][CH3:15])#[N:2].[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([NH:22][CH2:16][C:12]2[C:13]([CH2:14][CH3:15])=[C:8]([O:7][CH2:6][C:5]3[CH:4]=[C:3]([CH:21]=[CH:20][CH:19]=3)[C:1]#[N:2])[C:9]([CH3:18])=[N:10][CH:11]=2)=[CH:24][CH:25]=1)#[N:28]
Reactant: CCc1c(C=O)cnc(C)c1OCc1cccc(C#N)c1
Reactant: N#Cc1ccc(N)cc1
Product: CCc1c(CNc2ccc(C#N)cc2)cnc(C)c1OCc1cccc(C#N)c1
Yield: 52.3 %

Procedure:
The reductive amination of 3-(3-cyano-benzyloxy)-4-ethyl-2-methyl-pyridine-5-carbaldehyde (101) (700 mg, 2.50 mmol) and 4-aminobenzonitrile (2.0 g, 16.9 mmol), as described in Example 21, gave 3-{5-[(4-cyano-phenylamino)-methyl]-4-ethyl-2-methyl-pyridin-3-yloxymethyl}-benzonitrile (102) (500 mg, 52% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]=O)[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH:26][CH2:13][C:11]1[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=Cc1cn(-c2ccc(I)cc2)nc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1ccc(CNCc2cn(-c3ccc(I)cc3)nc2-c2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
1.34 g (3.581 mmol) of the product from Example 2A and 538 μl (3.581 mmol) of 2,4-dimethoxybenzylamine are dissolved in 40 ml of dichloroethane, and the mixture is stirred at room temperature for one hour. 1.52 g (7.162 mmol) of sodium triacetoxyborohydride and 820 μl (14.33 mmol) of glacial acetic acid are then added. The reaction mixture is stirred at room temperature for 15 hours. A saturated sodium bicarbonate solution is then added, and the product is extracted with dichloromethane. The organic extract is washed with water and dried over anhydrous sodium sulphate. After filtration, the solvent is removed on a rotary evaporator. The crude product is dried under high vacuum and used without further purification in the next reaction. What is obtained are 1.89 g of the title compound.
Reaction SMILES: [CH:1]([Si:4]([O:11][CH2:12][CH:13]([OH:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH3:24]I>>[CH:8]([Si:4]([O:11][CH2:12][CH:13]([O:23][CH3:24])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])([CH3:9])[CH3:10]
Reactant: CI
Reactant: CC(C)[Si](OCC(O)CNC(=O)OC(C)(C)C)(C(C)C)C(C)C
Product: COC(CNC(=O)OC(C)(C)C)CO[Si](C(C)C)(C(C)C)C(C)C
Yield: 62 %

Procedure:
Using a procedure analogous to Example 57-B, 3-(t-butoxycarbonylamino)-2-hydroxypropyl triisopropylsilyl ether and methyl iodide gave the title compound (13 g, 62%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].[CH2:15](I)[C:16]([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[CH3:15][C:16]([CH3:19])([CH3:18])[CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CC(C)(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1cc(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
1H-Indole-3-carboxylic acid (208 mg) was dissolved in N,N-dimethylformamide (10 ml), then sodium hydride (154 mg) was added thereto, and the mixture was stirred for 10 minutes at room temperature. Neopentyl iodide (0.25 ml) was added to the reaction solution and stirred for 15 hours at 80° C. Water was added to the reaction mixture which was then washed with ethyl acetate. The aqueous phase was adjusted to pH 6 by 1 N hydrochloric acid, extracted with ethylacetate, and the extract was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; n-hexane:ethyl acetate 4:1) to give the title compound (264 mg, Y.:89%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:21]([OH:23])=[O:22])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:14]([O:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([C:21]([OH:23])=[O:22])[CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OCc2ccccc2)C[C@H]1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1C[C@H](OCc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
(2S,4S)-1-(tert-butoxycarbonyl)-4-(benzyloxy)-pyrrolidine-2-carboxylic acid (Preparation 17, 150 mg, 0.47 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (5 ml) was added and the mixture left stirring overnight at room temperature. The reaction mixture was partitioned between dichloromethane (25 ml) and water (25 ml). The aqueous layer was separated, washed with more dichloromethane (25 ml) and evaporated to dryness. The product was purified using an ion exchange column (Dowex 50WX8-200 resin), eluting first with water then 9:1 water:ammonia yielding the title compound (34 mg, 33% yield) as a white solid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cnccn3)nc(NCCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)OC(C)C
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCN(C(=O)OC(C)C)c1ccc(Br)cc1C(=O)OC
Temperature: 25 °C
Yield: 89.7 %

Procedure:
Heat a suspension of methyl 5-bromo-2-isopropoxycarbonylaminobenzoate (10.0 g, 31.6 mmol), methyl 4-bromobutyrate (22.9 g, 126 mmol) and cesium carbonate (41.6 g, 126 mmol) in N,N-dimethylformamide (150 mL) under nitrogen at 80° C. for 24 h. Cool the mixture to room temperature and pour into water (200 mL). Extract with ethyl acetate (3×100 mL) and wash the organic extracts with water (3×100 mL) and brine (100 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as a colorless oil (11.8 g, 89%). 1H NMR (CDCl3, 300 MHz) δ 1.05-1.07 (m, 4H), 1.30-1.32 (m, 2H), 1.89-1.94 (m, 2H), 2.38-2.44 (m, 2H), 3.46-3.60 (m, 1H), 3.65 (s, 3H), 3.68-3.79 (m, 1H), 3.86 (s, 3H), 4.85-5.01 (m, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.62 (dd, J=1.7, 8.4 Hz, 1H), 8.07 (brs, 1H); ESI MS m/z 416 [C17H22BrNO6+H]+.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.Cl.[OH:13][NH2:14]>N1C=CC=CC=1.C(O)C.[Cl-].[NH4+]>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5](/[CH:6]=[N:14]/[OH:13])=[C:4]([F:11])[CH:3]=1
Reactant: NO
Reactant: O=Cc1cc(F)c(Br)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CCO
Product: O/N=C/c1cc(F)c(Br)cc1F
Yield: 53.5 %

Procedure:
A solution of 4-bromo-2,5-difluorobenzaldehyde (7.0 g, 31.67 mmol), hydroxyl amine hydrochloride (2.42 g, 34.84 mmol) in pyridine (35 mL) and ethanol (35 mL) was stirred at room temperature for 30 min. The reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine solution, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO2, eluting with 5-100% ethyl acetate in hexanes) to provide the title compound as a yellow solid (4.0 g, 53%): ESIMS m/z 238 [(M+2H)+].
Reaction SMILES: Cl[C:2]1[C:3]([CH3:14])=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[CH2:15]([OH:17])[CH3:16].[O-]CC.[Na+]>O>[CH2:15]([O:17][C:2]1[C:3]([CH3:14])=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:16]
Reactant: CCc1c(C)c(Cl)nn2c(N)nnc12
Reactant: CCO
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1nn2c(N)nnc2c(CC)c1C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
6-Chloro-8-ethyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.008, 273 mg) was dissolved in abs. ethanol (20 ml) while stirring. Thereafter, the reaction mixture was admixed with sodium ethoxide (176 mg) and stirred at RT for 3.5 h. After standing over the weekend, the solvent was drawn off, and the residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 230 mg of the title compound were obtained. LC-MS rt: 0.75 min [M+H]+: 222.2 (met. b)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1.[C:22](Cl)(=[O:24])[CH3:23]>>[C:22]([N:8]1[CH2:7][CH2:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([Cl:1])[CH:3]=3)[NH:11][C:10]=2[CH:9]1[C:15]1([C:19]([OH:21])=[O:20])[CH2:16][CH2:17][CH2:18]1)(=[O:24])[CH3:23]
Reactant: O=C(O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Reactant: CC(=O)Cl
Product: CC(=O)N1CCc2c([nH]c3ccc(Cl)cc23)C1C1(C(=O)O)CCC1

Procedure:
The procedure is as in Example 55, using as substrate the compound of Example 32 and as reagent acetyl chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:16]3[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]3)[N:12]=[C:11]([NH:26][CH:27]3[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]3)[N:10]=2)[CH2:5][C:4]([CH3:38])([CH3:37])[NH:3]1.[CH2:40]=[O:41].[OH-].[Na+]>C(O)(=O)C.O>[CH3:33][C:31]1([CH3:34])[CH2:32][CH:27]([NH:26][C:11]2[N:10]=[C:9]([NH:8][CH:6]3[CH2:5][C:4]([CH3:38])([CH3:37])[NH:3][C:2]([CH3:39])([CH3:1])[CH2:7]3)[N:14]=[C:13]([N:15]([CH:16]3[CH2:17][C:18]([CH3:24])([CH3:25])[NH:19][C:20]([CH3:22])([CH3:23])[CH2:21]3)[CH2:40][OH:41])[N:12]=2)[CH2:28][C:29]([CH3:36])([CH3:35])[NH:30]1
Reactant: C=O
Reactant: CC1(C)CC(Nc2nc(NC3CC(C)(C)NC(C)(C)C3)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CC(Nc2nc(NC3CC(C)(C)NC(C)(C)C3)nc(N(CO)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
54.3 g of 2,4,6-tris-(2,2,6,6-tetramethyl-4-piperidylamino)-1,3,5-triazine are dissolved in 200 ml of glacial acetic acid. After addition of 20 ml of 36% formaldehyde solution, the reaction mixture is stirred for 18 hours at room temperature, then diluted with water, made strongly alkaline with concentrated sodium hydroxide solution and extracted with toluene. The toluene solution is dried over sodium sulphate and concentrated in vacuo. Crystallisation of the residue yields 2,4-bis-(2,2,6,6-tetramethyl-4-piperidylamino)-6-(2,2,6,6-tetramethyl-4-piperidyl-methylolamino)-1,3,5-triazine in the form of colourless crystals with a melting point of 201°-202° C.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:18]=[C:19]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:20]3[N:26]=[CH:25][N:24]=[C:23]([SH:27])[C:21]=3[N:22]=2)[CH2:13][CH2:12]1)=[O:10]>[OH-].[Na+]>[CH2:1]([S:27][C:23]1[C:21]2[N:22]=[C:17]([N:14]3[CH2:15][CH2:16][N:11]([CH:9]=[O:10])[CH2:12][CH2:13]3)[N:18]=[C:19]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[C:20]=2[N:26]=[CH:25][N:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CN1CCN(c2nc(N3CCOCC3)c3ncnc(S)c3n2)CC1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=CN1CCN(c2nc(N3CCOCC3)c3ncnc(SCc4ccccc4)c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.7 ml (0.006 mol) of benzyl chloride were added dropwise to a solution of 1.8 gm (0.005 mol) of 2-(N-formylpiperazino)-8-mercapto-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 250°-255° C.) in about 60 ml of 0.1N sodium hydroxide. After stirring the mixture at room temperature for one hour, the precipitated reaction product was suction-filtered off, washed with water and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5](I)=[CH:4][N:3]=1.[C:14]([C:16]1[CH:17]=[N:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=1)#[CH:15].C(N(CC)CC)C>[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.CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=3)[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]=2[CH:7]=1
Reactant: C#Cc1cnn(C(=O)OC(C)(C)C)c1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
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: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2S(C)(=O)=O)cn1
Temperature: 60 °C

Procedure:
To a mixture of N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide (8) (419 mg, 1.11 mmol) and tert-butyl 4-ethynyl-1H-pyrazole-1-carboxylate (4) (277 mg, 1.44 mmol, 1.3 equiv) was added copper(I) iodide (7.4 mg 0.039 mmole) and DMF (4 mL), followed by triethylamine (0.69 mL, 497 mg, 4.92 mmol). The reaction was flushed twice with nitrogen. Bis(triphenylphosphine)palladium chloride (27 mg, 0.038 mmole) was added and the reaction flushed twice more with nitrogen, it was heated at 60° C. for 70 minutes. The reaction was added to water (40 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with water (3×20 mL) and with brine, dried and evaporated. The residue was purified on four 2 mm 20×20 cm silica prep tlc plates, eluted with 3:1 ethyl acetate:cyclohexane. The product band was recovered with acetone giving the title compound (251 mg, 51%). 1H-NMR (CDCl3, 500 MHz): δ 1.73 (s, 9H), 3.02 (s, 3H), 6.81 (s, 1H), 7.97 (s, 1H), 8.26 (s, 1H), 8.43 (s, 1H), 8.69 (s, 1H).
Reaction SMILES: C([O:5][C:6]([C@@:8]12[CH2:15][CH2:14][CH2:13][C@:12]1([Cl:16])[C:11](=[O:17])[N:10]([C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH2:9]2)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:16][C@:12]12[CH2:13][CH2:14][CH2:15][C@@:8]1([C:6]([OH:7])=[O:5])[CH2:9][N:10]([C@@H:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])[C:11]2=[O:17]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CCC[C@]2(Cl)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)O)CCC[C@]2(Cl)C1=O
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 87.3 %

Procedure:
A mixture of tert-butyl (1S,5R)-5-chloro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid (332 mg, 0.912 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (4 mL) was stirred for 14.5 hours at room temperature. The solvent was distilled off under reduced pressure. To the residue was added diethyl ether (3 mL), and then the precipitate was collected by filtration to afford 245 mg of the title compound as a colorless solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][N:26]1[C:30]2[CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CN(C=O)C.[F:43][C:44]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:45][O:46][C:47](=[O:67])[C@H:48]([OH:66])[CH2:49][C@H:50]([NH2:65])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[CH:59]=2)=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>>[F:72][C:44]([F:43])([C:68]([F:69])([F:70])[F:71])[CH2:45][O:46][C:47](=[O:67])[C@H:48]([OH:66])[CH2:49][C@H:50]([NH:65][C:35]([C:32]1[CH:33]=[CH:34][C:29]2[N:28]=[N:27][N:26]([OH:25])[C:30]=2[CH:31]=1)=[O:37])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[CH:59]=2)=[CH:54][CH:53]=1
Reactant: N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCC(F)(F)C(F)(F)F
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCC(F)(F)C(F)(F)F)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 7.1 %

Procedure:
HATU (37.9 mg, 99.6 μmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (14.9 mg, 83 μmol) in DMF (0.5 mL, 6.4 mmol) and the resulting mixture was stirred at room temperature for 5 minutes. (2R,4R)-4-Amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid 2,2,3,3,3-pentafluoropropyl ester (30.0 mg, 66.4 μmol) was added to the mixture, followed by DIPEA (35 μL, 0.2 mmol) dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo to yield a yellow liquid, which was purified by preparative HPLC to yield the title compound as a white solid (2.9 mg, purity 100%). MS m/z [M+H]+ calc'd for C27H22ClF5N4O5, 613.12. found 613.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH3:8])[N:7]=1.C(Cl)([Cl:14])=O>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[S:4][C:5]([C:9]([Cl:14])=[O:11])=[C:6]([CH3:8])[N:7]=1
Reactant: COc1nc(C)c(C(=O)O)s1
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: COc1nc(C)c(C(=O)Cl)s1
Reaction time: 2 h

Procedure:
In a similar apparatus to Example 1, 10.4 g (0.06 mole) of 2-methoxy-4-methylthiazole-5-carboxylic acid were suspended in 150 ml of chlorobenzene. Under heating and reflux, phosgene was blown at a rate of 400 ml/hr for 15 hours (0.27 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 10.9 g of 2-methoxy-4-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 95.0% and 90.0%, respectively. NMR (δCDCl 3/TMS, ppm): 2.70(3H,s), 3.85(3H,s).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[N:12][N:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:12][N:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(SCCCCC(=O)OCC)s2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(CSc2nnc(SCCCCC(=O)O)s2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
In 2 ml of 90% methanol was dissolved 0.20 g of ethyl 5-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]valerate obtained in Example 9 with heating at 60° C. Further 1.5 ml of a 1N aqueous sodium hydroxide solution was added to the solution followed by stirring at 60° C. for 30 minutes. An aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution to fractionate. The aqueous phase was made acidic with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with, in sequence, water, a saturated aqueous sodium chloride solution and then water and, dried over anhydrous magnesium sulfate. The solvent was then distilled off to give 0.18 g of oily 5-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]valeric acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[N:44]1([CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: C1COCCN1
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)n[nH]c12
Yield: 56.8 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indazole-7-carboxamide (Example 48a) (0.1 mmol) in DMF (2 mL) was reacted with K2CO3 (27.6 mg, 0.2 mmol), triethyl amine (83 uL, 0.6 mmol) and morpholine (43 uL, 0.5 mmol) to afford the title compound (29.4 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH:8]([OH:13])[C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(O)COc1ccc(Cl)cc1
Yield: 93.6 %

Procedure:
Into a 200-ml egg plant type flask were placed 9.0 g of 1-(p-chlorophenoxy)-3,3-dimethyl-2-butanone and 80 ml of methanol, and 0.8 g of sodium borohydride was further placed into the flask with cooling and stirring. After stirring the mixture at room temperature for 1 hour, the reaction mixture was concentrated in a vacuum, and 50 ml of water was added to the resulting residue, followed by extraction with 30 ml of ether twice. The combined ethereal extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The residue was purified by silica gel column chromatography, giving 8.5 g of the above-identified desired compound.