Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][C:16]#[N:17])=[CH:3][CH:2]=1.CCCCC.[H-].[Na+].Br[CH2:26][C:27]1[C:31]2[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=2[S:29][CH:28]=1>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]2[S:29][CH:28]=[C:27]([CH2:26][N:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[C:4]([O:14][CH2:15][C:16]#[N:17])[C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:31]=2[CH:32]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: N#CCOc1cccc2[nH]c3ccccc3c12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1c1ccccc1n2Cc1csc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
2-(9H-Carbazol-4-yloxy)acetonitrile (0.146 g, 0.66 mmol)) is added to a slurry of pentane-washed NaH (0.0441 g, 0.0011 mol) in DMF (1 mL) and allowed to stir for 20 min at room temperature. 3-(Bromomethyl)-5-chlorobenzothiophene (0.229 g, 0.88 mmol) is added and after stirring for 1 h the mixture is partitioned between ethyl acetate and water. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (75 mL) using ethyl acetate/hexane (20/80) and solids are precipitated using dichloromethane/hexane to give 0.148 g (56%) of the title compound; MS (ESI+) for C23H15ClN2OS m/z 425.2 (M+Na); IR (drift) 1581, 1460, 1439, 1332, 1279, 1232, 1221, 1155, 1148, 1115, 1079, 833, 780, 752, 717 cm−1; 1H NMR (CDCl3) δ5.10, 5.70, 6.72, 6.80, 7.12, 7.28-7.47, 7.80, 7.87, 8.36. Anal. Calcd for C23H15ClN2OS: C, 68.57; H, 3.75; N, 6.95. Found: C, 68.87; H, 4.22; N, 6.56.
Reaction SMILES: [CH2:1]([O:5][C:6]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)[C:2]#[C:3][CH3:4].[ClH:24]>C(OCC)(=O)C>[ClH:24].[CH2:1]([O:5][C:6]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:7][NH:8][CH2:9]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOC1(c2ccccc2C)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC#CCOC1(c2ccccc2C)CNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
2.8 g (9 mmol) of tert-butyl 3-but-2-ynyloxy-3-o-tolyl-azetidine-1-carboxylate are solubilised in 40 ml (120 mmol) of a 3M solution of hydrochloric acid in ethyl acetate. After stirring for 1 hour 30 minutes at ambient temperature, the reaction medium is concentrated under vacuum. 2.2 g of 3-but-2-ynyloxy-3-o-tolylazetidine hydrochloride are obtained in the form of a beige solid with a yield of 96%.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C@@H:21]([O:23][CH3:24])[CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:12][C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][C@@H:21]([O:23][CH3:24])[CH2:20][C@@H:19]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@@H](OC)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]1C[C@H](Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2F)[C@@H](c2ccnn2C)C1
Yield: 88.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4S*)-4-methoxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (60.0 mg, 0.0975 mmol) prepared in Example 120d, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (40.0 mg, 88%) as a colorless solid.
Reaction SMILES: Cl[C:2](Cl)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20]>CCOC(C)=O>[CH3:18][S:19]([N:22]=[C:2]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:21])=[O:20]
Reactant: ClC(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: CS(N)(=O)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Yield: 34.7 %

Procedure:
Dichlorodiphenoxymethane (2 g, 7.46 mmol) and methylsulfonamide (1.56 g, 16.41 mmol) were dissolved in EtOAc (15 ml) and heated to reflux for 12 hours. The mixture was allowed to cool and was concentrated under vacuum. Purification of the crude mixture by flash chromatography (20% EtOAc/hexanes) afforded diphenyl methylsulfonylcarbonimidate (0.75 g, 2.59 mmol, 35%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[S:7][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ccc(F)cc1
Product: Fc1ccc(-c2nc(CCl)cs2)cc1
Yield: 89 %

Procedure:
This compound was synthesized from 4-fluorothiobenzamide and 1,3-dichloroacetone as described in example 39 step 1 (0.65 g, yield 89%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.96-7.93 (m, 2H), 7.30 (s, 1H), 7.16-7.12 (t, J=8.7 Hz, 2H), 4.75 (s, 2H). MS (ESI) m/z: Calculated for C10H7ClFNS: 227.00. found: 228.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH3:11])[C:5]=1[Cl:12].C(O[N:20]=O)CC(C)C>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([Cl:12])=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][N:20]=[CH:11]2)=[O:13]
Reactant: CC(C)CCON=O
Reactant: COC(=O)c1ccc(N)c(C)c1Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]ncc2c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 4-amino-2-chloro-3-methyl-benzoic acid methyl ester (5.29 g, 26.5 mmol) in acetic acid (100 mL) was added isoamylnitrite (3.9 mL, 29.2 mmol). The reaction mixture was stirred at room temperature for 30 minutes then heated at reflux for 3 hours. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as an off-white solid (2.26 g, 40%). 1H NMR (CDCl3, 400 MHz) 3.97 (3H, s), 7.42 (1H, d, J=8.8 Hz), 7.95 (1H, d, J=8.8 Hz), 8.29 (1H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH:7]12[NH:12][CH:11]1[CH2:10][N:9]([C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=1[F:30])[CH2:8]2.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][CH2:3][C:4]([N:12]1[CH:11]2[CH:7]1[CH2:8][N:9]([C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=1[F:30])[CH2:10]2)=[O:5]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CC4NC4C3)c(F)c2)C(=O)O1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N1C2CN(c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)CC21
Reaction time: 1 h

Procedure:
Methoxyacetyl chloride (6 mL, 0.067 mmol) was added to a cooled (0° C.) solution of N-({(5S)-3-[4-(3,6-diazabicyclo[3.1.0]hex-3-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (15 mg, 0.05 mmol) in triethylamine (14 μL, 0.10 mmol) and dichloromethane (1.0 mL). After 1 hour, the solution was diluted with dichloromethane, and washed with dilute NaHCO3, brine, and dried (MgSO4), filtered and concentrated. Purification by pTLC (5% MeOH—CH2Cl2) provided the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[CH:3]([OH:17])[CH2:4][NH:5][C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=2)[CH2:8][CH2:7]1.[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([F:25])[CH:22]=1)[CH2:18][C@H:2]([NH:1][C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C@H:3]([OH:17])[CH2:4][NH:5][C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=2)[CH2:8][CH2:7]1
Reactant: CCc1cccc(C2(NCC(O)C(N)Cc3cc(F)cc(F)c3)CC2)c1
Reactant: O=C1CCC(=O)O1
Solvent: ClC(Cl)Cl
Product: CCc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)CCC(=O)O)CC2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-Amino-4-(3,5-difluoro-phenyl)-1-[1-(3-ethyl-phenyl)-cyclopropylamino]-butan-2-ol (0.500 g, 1.387 mmol) in chloroform (7 ml) was added TEA (0.58 ml, 4.161 mmol) with stirring under nitrogen for 30 min. To this solution was added succinic anhydride (0.138 g, 1.387 mmol) and reaction was stirred overnight at 50° C. The next morning reaction mixture was concentrated in vacuo, yielding the product. (ES+: 461.2)
Reaction SMILES: O.[CH3:2][N:3]([CH3:35])[CH:4]1[CH2:7][N:6]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[NH:26][CH:25]=4)[CH:21]=[CH:20][N:19]=3)=[C:10]([O:33][CH3:34])[CH:9]=2)[CH2:5]1.[NH4+].[Cl-]>[Fe].C(O)C>[CH3:35][N:3]([CH3:2])[CH:4]1[CH2:5][N:6]([C:8]2[CH:9]=[C:10]([O:33][CH3:34])[C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[NH:26][CH:25]=4)[CH:21]=[CH:20][N:19]=3)=[CH:12][C:13]=2[NH2:14])[CH2:7]1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 105 °C
Reaction time: 3 h
Yield: 107.9 %

Procedure:
Water (4 mL) was added to a mixture of N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 167, 240 mg, 0.52 mmol), iron (175 mg, 3.13 mmol), NH4Cl (19.56 mg, 0.37 mmol) and ethanol (24 mL). The resulting mixture was stirred at 105° C. for 3 h, and was then filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and part-purified by ion exchange chromatography, using an SCX column and eluting with 0.35M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo to give the title compound (241 mg, 107%) as a brown gum which was used without further purification; m/z: ES+ MH+ 430.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)=[O:5])C.[OH-].[K+].O>CO>[F:15][C:11]1[CH:10]=[C:9]([C@@H:7]2[CH2:8][C@H:6]2[C:4]([OH:5])=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1C[C@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of rac-trans 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid ethyl ester (13.0 g, 0.062 mol) in MeOH (310 mL) was added a solution of KOH (35.0 g, 0.625 mol) in MeOH (150 mL) at 0° C. After addition of the base the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into water and extracted with methylene chloride (2×50 mL). The aqueous layer was acidified with 10% HCl. The resulting mixture was extracted with methylene chloride (2×150 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness to give rac-trans-2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid as colorless crystals (9.5 g, 85%). Separation of the isomers by chiral SFC (Method D) gave the title compound (1S,2S)-2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid IM47 as colorless crystals (3.27 g, 17% overall yield from 3-fluorostyrene) sufficiently pure for the next step. Specific optical rotation +263.4° [α]D20 (C=1% MeOH)
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[S:18])[NH2:17]>C(O)C>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[S:18][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:17]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1ccccn1
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ccccn2)n1

Procedure:
16.3 ml of ethyl bromopyruvate were added dropwise to 15.9 g of the product of Stage B in 250 ml of ethanol and the mixture was refluxed for 5 hours. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica (eluant: hexane--AcOEt 1-1) to obtain 10.2 g of the expected product melting at 69.1° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(Cl)Cl.C1C=CC(N[S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])=CC=1>CN(C1C=CN=CC=1)C>[F:30][C:29]([F:32])([F:31])[S:26]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
Reaction time: 21 h
Yield: 96 %

Procedure:
To a stirred solution of dimethyl 4-hydroxyisophthalate T9.1 (commercially available from Chem Service) (37.7 g, 179 mmol) in DCM (256 mL, 179 mmol) at 23° C. was added TEA (30 mL, 215 mmol), and a catalytic amount of DMAP. N-phenyltriflamide (70 g, 197 mmol) was then added, and stirring was continued at room temperature for 21 hours. The solvent was removed, and the residue was purified on silica gel (0-10% EtOAc in hexanes) to yield T9.2 dimethyl 4-(trifluoromethylsulfonyloxy)isophthalate as a colorless oil (59.00 g, 96% yield). MS ESI (pos.) m/e: 360.0 (M+H2O)+, 343.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].[Br-].Cl.[CH3:13][CH2:14]OC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH:13]=[CH2:14])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC(O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,5-dichlorobenzaldehyde (7.5 g, 43 mmol) in THF (75 mL) was cooled to 0° C. and vinylmagnesiuin bromide (1M in THF, 48 mL, 48 mmol) was added dropwise. The reaction was warmed to room temperature and was stirred overnight. Aqueous HCl (1N) and EtOAc were added. The aqueous solution was extracted with EtOAc and the organic solution was dried (MgSO4), filtered, and concentrated. The residue was used in the next step without further purification.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]3[CH2:22][C@@H:21]([C:23](=[O:35])[NH:24][C@H:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH2:28][CH2:27][CH2:26]4)[N:20]([C:36](=[O:58])[C@@H:37]([NH:44][C:45](=[O:57])[C@@H:46]([N:48]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH3:49])[CH3:47])[CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[C:53]([O:52][C:50](=[O:51])[N:48]([C@H:46]([C:45](=[O:57])[NH:44][C@@H:37]([CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1)[C:36]([N:20]1[CH2:19][C@@H:18]([NH2:17])[CH2:22][C@H:21]1[C:23](=[O:35])[NH:24][C@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:58])[CH3:47])[CH3:49])([CH3:54])([CH3:55])[CH3:56]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
{(3S,5S)-1-{(S)-2-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-5-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-pyrrolidin-3-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester (Intermediate 25) (100 mg, 124 μM) was dissolved in DMF (0.9 mL) at room temperature and piperidine (0.1 mL) was added. The mixture was stirred at room temperature for 30 minutes, concentrated and the residue purified by chromatography over silica gel to give the title compound as white foam (56.7 mg, 78%). LC-MS: 585 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)OCc3ccc(Cl)cc3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(O)c1ccc(-c2ccc(C(=O)OCc3ccc(Cl)cc3)cc2)cc1
Temperature: 0 °C
Yield: 99.5 %

Procedure:
36.5 g (0.1 mol) of p-chlorobenzyl 4'-acetyl-4-biphenylcarboxylate, 150 ml of chloroform and 50 ml of ethanol were supplied into a four-necked flask equipped with a stirrer and a thermometer. Then 3.8 g (0.1 mol) of sodium borohydride was added at 15°-25° C. over a period of 10 minutes. The mixture was maintained at the same temperature for 2 hours. The reaction mixture was poured into ice-water and extracted twice with 200 ml of ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure to obtain 36.5 g (99.5% yield) of p-chlorobenzyl 4'-(1-hydroxyethyl)-4-biphenylcarboxylate (III-27).
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].P(Cl)(Cl)([Cl:15])=O>O>[Br:1][C:2]1[C:3]([Cl:15])=[N:4][CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc(C(F)(F)F)c1Br
Solvent: O
Product: FC(F)(F)c1ncnc(Cl)c1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
24.3 g (100.0 mmoles) of 5-bromo-4-hydroxy-6-trifluoromethylpyrimidine was suspended in 18.5 g (120.0 mmoles) of phosphorus oxychloride. The mixture was stirred at 100° C. for 2 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water gradually, followed by extraction with chloroform. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 21.5 g (yield: 82.4%) of 5-bromo-4-chloro-6-trifluoromethylpyrimidine.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7]Br.C(O)C>O>[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7][C:1]#[N:2]
Reactant: COc1ccc(Cl)c(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cl)c(CC#N)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sodium cyanide (10.4 g) was added portionwise to a stirred solution of the above benzyl bromide (25 g) in a 2:1 mixture of ethanol and water (250 ml). The mixture was stirred for one hour at 50° C., poured into water and extracted with ether. The extract gave 2-chloro-5-methoxy-phenylacetonitrile (m.p. 62°-65° C.). 10M Boranemethylsulphide complex (11.3 ml) was added dropwise under nitrogen to a refluxing solution of the above phenylacetonitrile (18.6 g) in tetrahydrofuran (150 ml). The mixture was heated under reflux for 2 hours and dilute hydrochloric acid was added dropwise and the acidified mixture heated at 95° C. for one hour. The cooled mixture was washed with ether, basified with dilute sodium hydroxide solution and extracted with ether. The extract yielded 2 -chloro-5-methoxyphenethylamine as a yellow oil.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].[CH2:11](Br)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:2][P:1]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:4]
Reactant: BrCCc1ccccc1
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(CCc1ccccc1)OCC
Temperature: -15 °C
Yield: 51.6 %

Procedure:
Diethyl phosphite (27.64 g, 200 m mole) was dissolved in DMF (200 ml), and to the solution at nitrogen atmosphere while stirring and -15° C., sodium hydride (60% in oil, 9.6 g, 220 m mole) was added. The mixture was stirred for 1 hour at not more than 0° C. To the solution phenethyl bromide (37.0 g, 200 m mole) was dropwise added and further the mixture was stirred overnight at room temperature. The DMF solution was distilled under reduced pressure leaving a residue, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated and the thus obtained oily product was distilled under reduced pressure to obtain diethylphenethylphosphonate (25.0 g, yield: 51.6%) of boiling point 136.5°~137.5° C./3 mmHg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][CH:38]1[CH2:40][O:39]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][N:12]([CH2:37][CH:38]([OH:39])[CH3:40])[N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[S:22][CH:23]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Reactant: CC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(O)Cn1ccc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 mg (0.022 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1H-pyrazol-3-yl)pyridine-3,5-dicarbonitrile were dissolved in 1 ml of 2-methyloxirane, and a spatula tip of cesium carbonate was added. The reaction mixture was stirred at room temperature overnight, concentrated, taken up in a little methanol and purified by preparative HPLC (acetonitrile/water: 10:90→95:5, 0.1% TFA added). This gave 10 mg (86% of theory) of the target compound.
Reaction SMILES: [CH2:1]([CH:8]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:17].BrBr>O>[Br:17][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]1=[O:14]
Reactant: O=C1NC(=O)C(Cc2ccccc2)C(=O)N1
Reactant: Br
Agent: BrBr
Solvent: O
Product: O=C1NC(=O)C(Br)(Cc2ccccc2)C(=O)N1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-benzylbarbituric Acid (1.7 g) in 15 ml of water, cooled to 0-5° C. 1 ml of 48% hydrobromic acid are added followed by the addition dropwise of 0.437 ml of bromine into the reaction mixture. After 1 hour under stirring at a temperature below 10° C. the solid which formed is separated by filtration and washed with water. 2.17 g of the product are obtained, m.p. 164-166° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:20])[CH3:19]>C(=S)=S>[C:18]([C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1)(=[O:20])[CH3:19]
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2sc3ccccc3c2c1

Procedure:
Dibenzothiophene (18.4 g.) and anhydrous aluminium chloride (13.3 g.) were mechanically stirred in carbon disulphide (100 ml.) while acetyl chloride (7.85 g.) in carbon disulphide (20 ml.) was added dropwise over 0.5 hr. The temperature of the mixture rose to 30° C. After a total of 4 hr. stirring the mixture was poured on to ice and extracted with chloroform. The extract was washed with sodium bicarbonate solution, dried with magnesium sulphate, and evaporated. The residue was distilled under vacuum and a fraction, b.pt. 160°-180° C. at 0.6 mm. Hg, was extracted by boiling with ether, and the residue recrystallised twice from methanol to give colourless crystals of 2-acetyldibenzothiophene m.pt. 97°-100° C.