Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)=O.[C:19]([O:23][C:24](=[O:36])[CH2:25][CH2:26][N:27]([CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[C:28]([NH2:30])=[S:29])([CH3:22])([CH3:21])[CH3:20]>CN1C(=O)CCC1>[C:19]([O:23][C:24](=[O:36])[CH2:25][CH2:26][N:27]([CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[C:28]1[S:29][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:7][CH:6]=2)[N:30]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: C[C@H]1CC[C@H](Oc2ccc(C(=O)CBr)cc2)CC1
Reactant: CC(C)(C)OC(=O)CCN(C(N)=S)C1CCCC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)CCN(c1nc(-c2ccc(O[C@H]3CC[C@H](C)CC3)cc2)cs1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 2-bromo-1-[4-(trans-4-methyl-cyclohexyloxy)-phenyl]-ethanone (764 mg, 3.44 mmol), 3-(1-cyclopentyl-thioureido)-propionic acid tert-butyl ester (935 mg, 2.46 mmol), NMP (6 mL) were combined as indicated in general procedure B. The reaction was stirred at room temperature overnight. After an aqueous work up, the crude product was purified by silica gel chromatography (gradient, hexane→3% EtOAc-hexane) to afford 3-(cyclopentyl-{4-[4-(trans-4-methyl-cyclohexyloxy)-phenyl]-thiazol-2-yl}-amino)-propionic acid tert-butyl ester (1.05 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:21])[C@@H:12]([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].[C:22]([O:26][C:27]([NH:29][C@H:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:21])[C@@H:12]([NH:20][C:31](=[O:32])[C@H:30]([NH:29][C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:28])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccccc2)n1
Reaction time: 0.08 h

Procedure:
A solution of 2-((S)-2-amino-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (prepared as described in example 3, step c) (0.61 g, 2.0 mmol), (R)-tert-butoxycarbonylamino-phenylacetic acid (0.55 g, 2.2 mmol), diisopropylethylamine (1.40 mL, 7.88 mmol) and 1-hydroxybenzotriazole (0.324 g, 2.40 mmol) in N,N-dimethylformamide (5 mL) was stirred in an ice bath for 5 minutes To the cooled yellow-orange solution was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexaflurorophosphate (0.91 g, 2.40 mmol). The reaction mixture was stirred for 5 minutes and the ice bath was removed and stirring continued for 1 hour. The reaction mixture was then diluted with ethyl acetate, washed brine and the aqueous layer extracted with ethyl acetate. The combined organic extracts were passed through a pad of sodium sulfate layered on the top of a pad of silica gel contained in a 60 mL vacuum filtration funnel. Residual material was eluted from the pad of sodium sulfate and silica gel with ethyl acetate and the filtrate was concentrated in vacuo to give —[(S)-2-((R)-2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-3-phenyl-propionylamino]-thiazole-4-carboxylic acid methyl ester which was taken into dry dichloromethane (10 mL) under argon and cooled in an ice bath. To this was added trifluoroacetic acid (5 mL, 64.9 mmol) and the mixture stirred at 0° C. for 2 hours. The reaction mixture was then concentrated to dryness. The residue was taken into dichloromethane and precipited with ether and the suspension was stirred for 15 minutes. The solid was isolated by filtration and washed with ether and dried to give a tan solid. The solid was taken into dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, concentrated and dried to give 2-[(S)-2-((R)-2-amino-2-phenyl-acetylamino)-3-phenyl-propionylamino]-thiazole-4-carboxylic acid methyl ester as an off white foam (0.80 g, 91%).
Reaction SMILES: [NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[OH:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1.[O:30]1[CH:35]=[CH:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:24]1
Reactant: C1=COCCC1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C1CCC(OC2CCCCO2)CC1

Procedure:
Pyridinium-4-toluenesulfonate (2.57 g, 10.2 mmol) was added to a solution of ethyl 4-hydroxycyclohexanecarboxylate (8.8 g, 51.10 mmol) and 3,4-dihydro-2H-pyran (8.60 g, 102 mmol) in DCM (200 mL). After 16 hours the reaction was quenched with saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was washed with water. The organic layer was dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography on an Analogix SF65-200 g column (hexanes/ethyl acetate 95:05-9:1) afforded the title compound (clear oil) as a mixture of isomers (11.1 g, 85%).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:31][S:32]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:38]4[CH2:39][CH2:40][CH:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: CS(=O)(=O)C1CCNCC1
Agent: Cl
Product: CS(=O)(=O)C1CCN(c2ccc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cn2)CC1

Procedure:
4-Methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and 4-methanesulfonyl piperidine hydrochloride. MS calcd. for C28H27ClN4O4S [(M+H)+] 551.1, obsd. 551.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:6][C:5]=1[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([O-])=O>[Pd].C1(C)C=CC=CC=1.CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)=[CH:6][C:5]=1[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Oc3ccccc3)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Oc3ccccc3)cc2)ccc1N
Yield: 89.9 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[2-nitro-5-(4-phenoxyphenoxy)phenyl]-N-methylcarbamate (8.6 g), palladium on carbon (10%, 0.6 g) and toluene/methanol=16/3 (190 ml) and the reaction mixture was purified to give the title compound (7.2 g).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([O:18][C:19](=[O:25])[NH:20][CH:21]1[CH2:24][NH:23][CH2:22]1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19](=[O:25])[NH:20][CH:21]1[CH2:24][N:23]([CH:10]2[CH2:11][CH2:12][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH2:22]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Product: CC(C)(C)OC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-phenyl-cyclohexanone and azetidin-3-yl-carbamic acid tert-butyl ester using the procedure described in Step D of Example 1.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1.ClCCl>N1C=CC=CC=1>[CH3:16][C:17]1[CH:21]=[C:20]([NH:22][S:12]([C:9]2[CH:10]=[CH:11][C:6]([C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2cc(C)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 54.5 %

Procedure:
A mixture of 4-t-pentylbenzenesulfonyl chloride (0.13 g, 0.53 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.10 g, 0.44 mmol) in pyridine (1.0 mL) was heated at 80° C. for 3 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.11 g, 0.24 mmol, 55%). 1H NMR (400 MHz, CDCl3) δ 8.96 (dd, J=1.6, 4.8 Hz, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 7.54 (dd, J=4.8, 8.4 Hz, 1H), 7.46-7.43 (m, 3H), 6.02 (s, 1H), 2.32 (s, 3H), 1.70 (q, J=7.2 Hz, 2H), 1.34 (s, 6H), 0.70 (t, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C24H27N4O2S [M+H]+ 435.2. found 435.1.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C@:5]2([CH2:22][C@H:21]([OH:23])[C@@:20]3([F:24])[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH:17]=[CH:16][C:15](=[O:25])[CH:14]=4)[C@@H:7]2[CH2:8][CH:9]=1)[CH3:6])[CH3:2].[Br:26]N1C(=O)CCC1=O>ClCCl>[Br:26][C:9]1[CH2:8][C@H:7]2[C@H:10]3[C@:20]([F:24])([C@@H:21]([OH:23])[CH2:22][C@:5]2([CH3:6])[C:4]=1[S:3][CH2:1][CH3:2])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3
Reactant: O=C1CCC(=O)N1Br
Reactant: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Solvent: ClCCl
Product: CCSC1=C(Br)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (11β)-17-(ethylthio)-9-fluoro-11-hydroxyandrosta-1,4,16-trien-3-one (181 mg) in dichloromethane (10 ml) containing N-bromosuccinimide (98 mg) is stirred at room temperature for 2 hours and the reaction mixture is subjected to preparative thin layer chromatography on silica gel plates to isolate the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]2)=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C=O.[C:22]([BH3-])#N.[Na+].O>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH3:22])=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1ccc(NC(=O)[C@H]2CCCCN2)cc1[N+](=O)[O-]
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCCC[C@@H]1C(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 98.7 %

Procedure:
(R)—N-(4-Amino-3-nitrophenyl)piperidine-2-carboxamide (2.09 g, 7.9 mmol) was dissolved in MeOH (50 mL), and paraformaldehyde (0.95 g) and sodium cyanoborohydride (0.50 g, 8.0 mmol) were added. The mixture was stirred at room temperature for 70 min, and water added dropwise. The solvent was evaporated and the residue partitioned between water and EA (150 mL each). The phases were separated and the aqueous phase extracted with EA (2×100 mL). The combined EA layers were washed with brine, dried over magnesium sulfate, and concentrated to give (R)—N-(4-amino-3-nitrophenyl)-1-methylpiperidine-2-carboxamide as an orange foam (2.17 g), which was used without purification.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:12][Si:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][O:8][CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:24][CH:25]=1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2nc3ccccc3n2COCC[Si](C)(C)C)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 100.5 %

Procedure:
A mixture of 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (8.7 g), tert-butyl 4-hydroxyphenylcarbamate (6.4 g) and cesium carbonate (20 g) in DMF (60 mL) was stirred at 60° C. for 24 h. After cooling to room temperature, to the mixture was added SiO2, the mixture was evaporated, and then the residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give tert-butyl {4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}carbamate (14 g) as brown oil.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(O)(=O)C.[C:26]([O:30][C:31](=[O:37])[N:32]([CH3:36])[CH2:33][CH:34]=O)([CH3:29])([CH3:28])[CH3:27].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[C:26]([O:30][C:31](=[O:37])[N:32]([CH2:33][CH2:34][NH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:20]=[CH:19]2)[CH3:36])([CH3:29])([CH3:28])[CH3:27]
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(CCNc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of (R)—N2-indan-1-yl-quinoline-2,6-diamine (453 mg, 1.645 mmol) in Methanol (10 mL) with acetic acid (0.3 mL, 4.935 mmol) and commercially available methyl-(2-oxo-ethyl)carbamic acid tert-butyl ester (300 mg, 1.731 mmol) was stirred at 23° C. for 1 h. Portionwise addition of sodium cyanoborohydride (286 mg, 4.11 mmol) was followed by additional stirring at 23° C. for 3 h. Poured onto saturated NaHCO3-solution and extracted twice with ethyl acetate, dried over Na2SO4 and evaporated totally gave a crude product which was purified by flash chromatography with heptane and ethyl acetate to give the title compound as a yellow foam (550 mg, 73%); MS: m/e=433.4 (M+H+).
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]=[CH:11][CH:10]=1)=[O:5])C.[Li+].[OH-]>CCO>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[C:4]([OH:5])=[O:3])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Yield: 90.1 %

Procedure:
To a stirred mixture of 33 (153 g, 804.25 mmol, 1.00 equiv) in EtOH (1 L) was added 1M aq. LiOH (1 L), and the resultant solution was stirred at reflux for 1 h. Volatile solvent was removed under reduced pressure and the residue diluted with EtOAc (1.5 L). The organic phase was washed with water (3×1 L) and brine (1×1 L), dried (Na2SO4), filtered and concentrated in vacuo to afford 117.5 g (90%) of trans-2-phenylcyclopropane-1-carboxylic acid (35) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[CH3:15][CH:16]1[CH2:21][NH:20][CH2:19][CH2:18][NH:17]1>CS(C)=O.O>[CH3:15][CH:16]1[CH2:21][N:20]([CH2:14][CH:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[OH:13])[CH2:19][CH2:18][N:17]1[CH2:14][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[OH:13]
Reactant: CC1CNCCN1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C(O)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)C(C)C2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (700 mg, 3.684 mmol) and 2-methylpiperazine (184 mg, 1.842 mmol) in 2 mL DMSO was heated under microwave condition (150° C.) for 1 hr. After cooling to rt., the mixture was diluted with water (50 mL), extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated. The residue was purified by prep-HPLC to obtain two peaks (peak 1 and peak 2). Each peak was further separated by SFC chiral chromatography to obtain three chiral isomers for each (of 8 isomers six were obtained, though two may be mixtures of 2 isomers).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([F:37])[CH:28]=4)[CH:24]=[C:23]([C:38]([F:41])([F:40])[F:39])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:37][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([C:38]([F:39])([F:41])[F:40])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[C:33]([F:34])([F:36])[F:35]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(F)c4)cc(C(F)(F)F)n3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(F)c4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.4 %

Procedure:
To a cooled and stirred solution of 3′-[4-(3-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.47 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.27 g, 50%). MS (ISP) 542.1 [(M+H)+]; mp 227.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2(O)[CH2:14][N:13]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CS([Cl:33])(=O)=O>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([Cl:33])[CH2:14][N:13]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 18 h

Procedure:
To a stirred solution of compound (9) (6.23 g) and N,Ndiisopropylethylamine (3.5 mL) in dichloromethane (100 mL) at 0° C. was added, dropwise, methanesulfonyl chloride (1.4 mL). The mixture was stired at 0° C. for 18 hrs, then washed (water, brine), dried (Na2SO4) and concentrated in vacuo. The crude product was recrystallised from hexane to give 3-(4-tert-butylphenyl)-3-chloro-1-(diphenylmethyl)azetidine (10) (4.73 g) m.p. 145° C. (hexane). Found: C, 80.30; H, 7.05; N, 3.64. C26H28CIN requires C, 80.08; H. 7.24; N, 3.59%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:3]=1.[Li]CCCC.C[O:17][B:18](OC)[O:19]C>C1COCC1>[CH2:8]([C:4]1[CH:3]=[C:2]([B:18]([OH:19])[OH:17])[CH:7]=[CH:6][CH:5]=1)[CH2:9][CH3:10]
Reactant: COB(OC)OC
Reactant: CCCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
To a solution of Intermediate 214.1 (130 mg, 0.65 mmol) in 4 mL THF at −78° C., was added BuLi (1.4 M in hexanes, 0.557 mL, 0.78 mmol). The mixture was stirred 5 min at −78° C., then trimethylborate (0.109 mL, 0.975 mmol) was added. The reaction was stirred at −78° C. for 10 min, then was removed from the cooling bath and stirred 1 h. The reaction was quenched with 1 N HCl, then was diluted with EtOAc. The organic phase was washed with 1N HCl and brine, dried (Na2SO4) and concentrated to afford 83 mg of Intermediate 214.2 as a colorless oil, which was used without further purification in the following step.
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:5]=2[NH:4][C:3]1=[O:20].[CH3:21][C:22]1([NH:28][C:29](=[O:32])[CH2:30]I)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:21][C:22]1([NH:28][C:29](=[O:32])[CH2:30][N:4]2[C:5]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:6]=3[CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:8][CH:2]([Br:1])[C:3]2=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccc2c(c1)NC(=O)C(Br)CC2c1ccccc1
Reactant: CC1(NC(=O)CI)CCCCC1
Product: Cc1ccc2c(c1)N(CC(=O)NC1(C)CCCCC1)C(=O)C(Br)CC2c1ccccc1

Procedure:
Prepared as in Example 20I from 3-bromo-5-phenyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one using N-(1-methylcyclohexyl)-iodoacetamide, M.P. x° C., x% yield for the trans isomer.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][NH2:14]>>[NH:13]([C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:14]
Reactant: NN
Reactant: Cc1cc(Cl)nc2ncccc12
Product: Cc1cc(NN)nc2ncccc12
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-methyl-1,8-naphthyridine (330 mg, 1.8 mmol) in NH2NH2 was refluxed at 130° C. for 2 hours. The reaction mixture was cooled to room temperature, then excess NH2NH2 was removed on the rotary evaporator. The residue was taken up in 20 mL of CH2Cl2. The mixture was washed with saturated NaHCO3 (3×15 mL), brine (lx 20 mL), and then dried over MgSO4 and concentrated. The residue was washed with hexane to give 2-hydrazinyl-4-methyl-1,8-naphthyridine. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.56 (s, 3 H) 6.66 (s, 1 H) 7.22 (dd, J=7.91, 4.40 Hz, 1 H) 8.11 (dd, J=8.06, 1.90 Hz, 1 H) 8.82 (dd, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([O:15]C)=[O:14])=[N:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1>[NH2:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[N:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(-c2nccs2)ccc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(-c2nccs2)nc1C(=O)O
Temperature: 60 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a solution of methyl 3-amino-6-(thiazol-2-yl)picolinate (1.0 equiv) in THF (0.5M), was added 1M LiOH (4.0 equiv). After stirring for 4 hours at 60° C., 1 N HCl (4.0 equiv.) was added and the THF was removed in vacuo. The resulting solid was filtered and rinsed with cold H2O (3×20 mL) to yield 3-amino-6-(thiazol-2-yl)picolinic acid (61%). LCMS (m/z): 222.1 (MH+); LC Rt=1.9 min.