Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([N:14](C)[C:15](=O)C)=[CH:13][C:8]=3[N:7]=[C:6]2[CH:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)[CH3:20])[CH2:3][CH2:2]1.[OH-].[K+]>CCO>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH:14][CH3:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH3:29])=[CH:25][CH:26]=2)[CH3:20])[CH2:3][CH2:2]1
Reactant: CCOc1ccc(C(C)c2nc3cc(N(C)C(C)=O)ccc3n2CC2CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(C(C)c2nc3cc(NC)ccc3n2CC2CC2)cc1
Yield: 97.9 %

Procedure:
A mixture of N-[1-(cyclopropylmethyl)-2-[1-(4-ethoxyphenyl)ethyl]-1H-benzimidazol-5-yl]-N-methyl acetamide (2.43 g, 5.64 mmol) and 40% KOH (50 ml) in EtOH was heated for 20 h at reflux. After being cooled down, the mixture was concentrated to a small volume (50 mL) and diluted with H2O (50 mL) which was extracted with dichloromethane (4×50 mL). The combined organic phases were dried with Na2SO4. After filtration and evaporation of the solvent, the residue was purified by MPLC using EtOAc on silica gel to give 1.93 g (99%) of the title compound as an off-white solid. MS (ESI) (M+H)+=350.37.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C@@H:8]([OH:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>>[CH3:21][S:18]([O:10][C@@H:8]([CH3:9])[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[OH:11])(=[O:20])=[O:19]
Reactant: C[C@H](O)C(O)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Product: C[C@H](OS(C)(=O)=O)C(O)(c1ccccc1)c1ccccc1

Procedure:
By treating (S)-1,1-diphenyl-1,2-propanediol with mesyl chloride, (S)-2-methanesulfonyloxy-1,1-diphenyl-1-propanol was obtained. Namely, as a result of the treatment of (S)-1,1-diphenyl-1,2-propanediol with CH3SO2Cl (1.2 equivalent)-(C2H5)3 -N(1.5 equivalent) at 0° C. in CH2Cl2, (S)-2-methanesulfonyloxy-1,1-diphenyl-1-propanol was obtained in a yield of 87% (the position selectivity of this sulfonylation reaction was more than 95% from the measurement with 1H NMR).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>>[C:34]1([O:33][C:31](=[O:32])[N:14]([C@@H:13]2[C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Oc1ccccc1
Product: CN(C(=O)Oc1ccccc1)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid phenyl ester was prepared from rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using phenyl chloroformate instead of 4-fluorophenyl chloroformate and was obtained as a light brown foam. MS m/e: 558.0 [M]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(=O)O[CH2:10][CH2:9][O:8]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:10][CH2:9][OH:8])=[C:16]([O:21][CH3:22])[CH:15]=1
Reactant: COc1cc(Br)ccc1O
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Br)ccc1OCCO
Temperature: 115 °C
Yield: 82.6 %

Procedure:
Potassium carbonate (1.4 g, 10 mmol) was added to a solution of ethylene carbonate (1.8 g, 20 mmol) and 4-bromo-2-methoxyphenol (1.05 g, 5 mmol) in 5 mL of toluene under an inert atmosphere. The reaction was heated at 115° C. for 12 h. Water (50 mL) and ethyl acetate (2×100 mL) were added to the reaction mixture to stir. The organic layers were combined, dried, filtered, and evaporated to get a yellow oil residue. The residue was purified by flash chromatography (eluting with 40→45% EtOAc in hexanes) to give compound 8a as a light brown yellow oil (1 g; 4.13 mmol; 82.6% yield); MS (APCI) (M+H)+ 246. 1H NMR (400 MHz, chloroform-D) δ ppm 2.83 (t, J=6.3 Hz, 1H) 3.84 (s, 3H) 3.89-4.01 (m, 2H) 4.03-4.13 (m, 2H) 6.78 (d, J=8.3 Hz, 1H) 6.99 (d, 1H) 7.02 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:33][CH2:32]1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:44][C:41]3[CH:40]=[CH:39][C:38]([CH2:37][N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)=[CH:43][CH:42]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CN4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 15.5 %

Procedure:
8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.098 g, 0.24 mmol) and 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (0.049 g, 0.24 mmol) were combined in i-PrOH (2 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 20 mg of 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.36 (s, 1H), 8.54 (s, 1H), 7.43 (d, 2H, J=7.9 Hz), 7.29 (m, 2H), 7.18 (dd, 2H, J=2.0 Hz, J=7.9 Hz), 7.03-7.05 (m, 1H), 4.38 (q, 2H, J=7.1 Hz), 3.44 (s, 2H), 3.08 (t, 2H, J=7.4 Hz), 3.01 (t, 2H, J=7.5 Hz), 2.52 (br s, 8H), 2.36 (s, 3H), 2.19-2.29 (m, 2H), 1.39 (t, 3H, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:13]O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(F)cc1
Yield: 81 %

Procedure:
A solution of 2-(4-fluorophenyl)acetic acid (15.4 g, 0.1 mol) in methanol (600 mL) was treated with a solution of hydrogen chloride in dioxane (4 N, 100 mL) followed by warming at reflux for 18 h. The solution was cooled and concentrated in vacuo. The residue was distilled under reduced pressure (55-58° C./0.5 mm Hg) to afford the title compound as colorless oil (13.6 g, 81%). 1H NMR (300 MHz, CDCl3): δ 3.60 (s, 2 H) 3.70 (s, 3 H) 7.02 (m, 2 H) 7.24 (m, 2 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][NH2:11].Cl>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[C:18]([O:17][C:15]([NH:8][C@@H:9]([CH2:10][NH:11][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[C:12]([OH:14])=[O:13])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)CCCCl)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
4-Chlorobutanoyl chloride (12.1 g, 86 mmol) was added to a solution of Boc-L-Dap (16.0 g, 78 mmol) in dioxane (160 mL) and 10% aqueous Na2CO3 (180 mL) at 0° C. dropwise. The reaction mixture was stirred at 0° C. for 1 h and then allowed to warm to ambient temperature and stirred overnight. The mixture was acidified with 1N aqueous hydrochloric acid to pH=3 and extracted with EtOAc (300 mL×3). The combined organic phases were washed with 1N aqueous hydrochloric acid (300 mL×3) and brine (300 mL×1), dried over anhydrous sodium sulfate, and concentrated to afford (S)-2-(tert-butoxycarbonylamino)-3-(4-chlorobutanamido)propanoic acid (15.5 g, 64% yield), which was used directly without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=2)=[O:34])[NH:14][C@H:15]([CH3:31])[C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[N+:1]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:32][C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=2)=[O:34])[NH:14][C@H:15]([CH3:31])[C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCNC1

Procedure:
To a solution of the compound (1.087 g), which had been obtained in (1), in anhydrous dichloromethane (5 ml), trifluoroacetic acid (2 ml) was added dropwise under ice cooling. The resulting mixture was treated in a similar manner to that described in Referential Example 16-(2), whereby the title compound was obtained. The product was provided for use in the subsequent reaction without isolation, Infrared absorption spectrum (KBr) νmax cm-1 : 3290, 1739, 1674, 1645, 1625, 1555, 1524.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:14][OH:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12].[F:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29]Br)=[CH:23][CH:22]=1>C1COCC1>[F:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][O:15][CH2:14][CH:13]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH3:12])=[C:4]([Cl:3])[CH:5]=2)[C:16]([F:17])([F:18])[F:19])=[CH:23][CH:22]=1
Reactant: Fc1ccc(Oc2cccc(CBr)c2)cc1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(COCc2cccc(Oc3ccc(F)cc3)c2)C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 35.6 %

Procedure:
Under a nitrogen atmosphere, 60 mg of sodium hydride (60% oil dispersion) was added to 10 ml of dry THF. A solution of 0.41 g of 2-(3-chloro-4-ethoxyphenyl)-3,3,3-trifluoropropanol and 1.43 g of 3-(4-fluorophenoxy)benzyl bromide in 10 ml of dry THF was then added with ice-cooling, and the reaction solution was stirred with ice-cooling for 1 hour and at room temperature for 12 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (40:1) mixture] to obtain 255 mg of the desired compound.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:40][CH3:41])[C:5](=[O:39])[CH:6]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[O:32])=[CH:26][CH:25]=1)[C:7]([NH:9][S:10]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)(=[O:12])=[O:11])=[O:8])[CH3:3].[CH3:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]2[C@:51]3([CH3:62])[C@@H:56]([CH2:57][CH2:58][C:47]=2[CH:46]=1)[C@@:55]([CH2:60][NH2:61])([CH3:59])[CH2:54][CH2:53][CH2:52]3>CO>[CH3:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]2[C@:51]3([CH3:62])[C@@H:56]([CH2:57][CH2:58][C:47]=2[CH:46]=1)[C@@:55]([CH2:60][NH2:61])([CH3:59])[CH2:54][CH2:53][CH2:52]3.[CH2:40]([N:4]([CH2:2][CH3:3])[C:5](=[O:39])[C@H:6]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[O:32])=[CH:26][CH:25]=1)[C:7]([NH:9][S:10]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)(=[O:11])=[O:12])=[O:8])[CH3:41]
Reactant: CCN(CC)C(=O)C(Cc1ccc(NC(=O)c2ccccn2)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Agent: CCCc1ccc2c(c1)CC[C@H]1[C@](C)(CN)CCC[C@]21C
Agent: Cl
Solvent: CO
Product: CCN(CC)C(=O)[C@H](Cc1ccc(NC(=O)c2ccccn2)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1

Procedure:
Resolution in the same manner as in Example 91 and using a free form of the compound (18.2 g) obtained in Example 60, (+)-dehydroabiethylamine (12.1 g) and methanol gave a (+)-dehydroabiethylamine salt (12.3 g) (optical purity>98% d.e.) of the title compound as white crystals. The salt was desalted with 2 equivalent amounts of hydrochloric acid in the same manner as in Example 91 to give the title compound (4.81 g) as a white solid (optical purity>98% e.e.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([N:7]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([N:7]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:29])[CH3:6])[CH3:2]
Reactant: CCOC(=O)[C@@H](C)N1C(=O)COc2cc(Br)ccc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](C)N1C(=S)COc2cc(Br)ccc21
Temperature: 25 °C
Yield: 119.4 %

Procedure:
A solution of (R)-2-(7-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (80 g, 244 mmol) and Lawesson's reagent (59.1 g, 146 mmol) in toluene (900 mL) was heated at reflux for 3 h then cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give (R)-2-(7-bromo-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (60 g, 71%) as a yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.20 (s, 1H), 7.12 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.70 (m, 1H), 4.99-4.88 (m, 2H), 4.23-4.15 (m, 2H), 1.57 (d, J=7.2 Hz, 3H), 1.16 (t, J=7.2 Hz, 3H). SFC (Table 1, Method 30) Rt=2.902 min.; [α]D20=20.79 (C=0.002 g/mL in methanol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH:18]1([NH2:22])[CH2:21][CH2:20][CH2:19]1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:18]2[CH2:21][CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: NC1CCC1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1nc(NC2CCC2)c2c(n1)C(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (160 mg, 0.60 mmol) in NMP (2 mL) was added cyclobutanamine (129 mg, 1.81 mmol) dropwise. The mixture was stirred at RT for 3 hrs. 8 mL of water was added to precipitate out the product. The solid was filtered out and air-dried to give a crude 2-chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (177 mg, 0.57 mmol, 94% yield), which was used for the next step without any purification. LC-MS (M+H)+=300.1
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[C:15]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)[CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC2C3C(C(=O)N(C4C=CC([Cl:47])=CC=4)N=3)=CNC=2C=1>>[Cl:47][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[C:15]([N:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]5)[CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)=[CH:2][CH:3]=1
Reactant: Nc1ccc2c3nn(-c4ccc(Cl)cc4)c(=O)c-3c[nH]c2c1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)ccc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3cc(N4CCNCC4)ccc3c-2nn1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared following the procedure for 14a using 13b. 1H-NMR (DMSO-d6) δ (ppm): 3.07 (2H, br), 3.38 (4H, br), 3.48 (2H, br), 7.12 (1H, br), 7.48 (3H, m), 8.07 (1H, d, J=9.06 Hz), 8.25 (2H, dd, J=9.07, 2.20 Hz), 8.62 (1H, d, J=6.32 Hz). m/z 380.9 (MH+).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[N:33]=[CH:34][C:35]2[CH:40]=[CH:39][NH:38][C:36]=2[N:37]=1>>[C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:32]3[N:33]=[CH:34][C:35]4[CH:40]=[CH:39][NH:38][C:36]=4[N:37]=3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ncc2cc[nH]c2n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2ncc3cc[nH]c3n2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide and 2-bromo-7H-pyrrolo[2,3-d]pyrimidine. MS (ESI): mass calcd. for C22H21FN4O2S, 424.14; m/z found, 425.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 9.31 (s, 1H), 8.82 (s, 1H), 8.15 (m, 1H), 7.90 (d, J=3.6, 1H), 7.68 (d, J=7.5, 1H), 7.63 (d, J=6.3, 1H), 7.50 (s, 1H), 7.42 (d, J=7.1, 1H), 7.02 (d, J=3.6, 1H), 6.66 (d, J=3.6, 1H), 1.12 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15]CC)=[O:14])=[CH:7]2)([O-:3])=[O:2].[OH-].[Na+]>C1COCC1.CO.O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a stirred solution of ethyl-5-nitroindole-2-carboxylate (8) (25.0 g, 106.8 mmol), in 500 mL of THF-methanol (1:1, v/v) at room temperature, was added a solution of NaOH (40 g, 1.0 mmol) in 300 mL of water. The resulting deep red-brown solution was stirred for 3 h, then quenched by acidification to pH 1 with dilute HCl. The precipitated product was collected by vacuum filtration, and the remaining dissolved product was extracted with T HF/ethyl acetate (1:2, v/v, 2×400 mL). The precipitate was dissolved in THF and this solution was combined with the organic layers from the extractions, supra. Drying over magnesium sulfate, filtration, concentration in vacuo, and crystallization of the residue from THF/ethyl acetate/hexane afforded 21.1 g (96% yield) of 5-nitroindole-2-carboxylic acid (9). 1H NMR (DMSO), 11.50 (s, 1H), 7.20 (d, 1H, J=8.4 Hz), 6.85 (s, 1H), 6.70 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH2:7][CH2:8][OH:9])[N:6]=1.O[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Br:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH2:7][CH2:8][O:9][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)[N:6]=1
Reactant: Cc1sc(Br)nc1CCO
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(Br)sc3C)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.2 %

Procedure:
To a solution of Example 173 (975 mg, 4.39 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (1.06 g, 4.83 mmol) in THF (20 mL) were added Ph3P (1.88 g, 7.46 mmol) and ADDP (1.96 g, 7.46 mmol). The mixture was vigorously stirred at rt for 72 hours, the solvent removed under reduced pressure, and the residue purified by silica gel flash chromatography (6:1 hexanes/EtOAc) to yield the product (1.4 g, 76%) as a colorless oil that solidifies upon standing. (C19H22BrNO3S) LC-MS, RT 3.92 min., M+H 424.5; 1H NMR (CDCl3): δ 1.26 (t, 3H), 1.65-1.81 (m, 1H), 2.28-2.45 (m, 2H), 2.37 (s, 3H), 2.69 (dd, 1H), 2.75-2.93 (m, 2H), 3.07 (t, 2H), 3.44-3.56 (m, 1H), 4.15 (t, 2H), 4.18 (q, 2H), 6.67 (dd, 1H), 6.73 (d, 1H), 7.03 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:3]=1[CH2:17][C:18]([OH:20])=O>O>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]2[S:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[CH2:17][C:18](=[O:20])[C:14]=2[CH:13]=1
Reactant: COc1ccc(Sc2cccc(Cl)c2CC(=O)O)cc1
Solvent: O
Product: COc1ccc2c(c1)C(=O)Cc1c(Cl)cccc1S2
Temperature: 110 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
The mixture of 30 g of 2-chloro-6-(p-methoxyphenylthio)-phenylacetic acid and 300 g of polyphosphoric acid was stirred at 110° C. for 3 hours. After cooling, to the mixture was added water and the mixture was extracted with chloroform. The extract was washed with 1 N sodium hydroxide solution, saturated sodium chloride solution, dried over anhydrous sodium sulfate and freed of the solvent to afford 22.9 g (81%) of 2-methoxy-9-chloro-10,11-dihydrodibenzo[b,f]thiepin-11-one as reddish crystals having a melting point of 117°-120° C.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][C:23]1[O:24][C:25](=O)[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>C(O)(=O)C>[CH3:22][C:23]1[N:21]([C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([N:9]4[CH2:10][CH2:11][C@@H:7]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:8]4)[S:13][C:14]=3[CH:20]=2)[C:25](=[O:24])[C:26]2[C:27](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:28]=1
Reactant: Nc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Reactant: Cc1nc2ccccc2c(=O)o1
Solvent: CC(=O)O
Product: Cc1nc2ccccc2c(=O)n1-c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1

Procedure:
A solution of (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-amine (Example 89A, 27mg, 0.089 mmol) and 2-methyl-4H-benzo[d][1,3]oxazin-4-one (Example 89B, 14.39 mg, 0.089 mmol) in acetic acid (1 mL) was heated in a microwave reactor to 160° C. for 20 minutes. The mixture was concentrated under reduced pressure and chromatographed on silica gel column eluting with 2% (9:1 methanol:concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.45-1.53 (m, 2H), 1.58-1.70 (m, 4H), 1.98-2.12 (m, 1H), 2.26-2.30 (m, J=1.36 Hz, 3H), 2.29-2.37 (m, 1H), 2.42-2.58 (m, 4H), 2.94-3.10 (m, J=8.48 Hz, 1H), 3.39-3.51 (m, 1H), 3.52-3.64 (m, 1H), 3.71-3.94 (m, 2H), 7.14 (dd, 1H), 7.43-7.51 (m, 2H), 7.66-7.72 (m, 2H), 7.74-7.81 (m, 1H), 8.24-8.31 (m, 1H); MS (DCI/NH3) m/z 387 (M+H)+.