Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]1([CH:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc2c1CCC2(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc2c1C=CC2c1ccccc1
Yield: 66.7 %

Procedure:
To 1 L of toluene was added 14 g (0.058 mol) of 4-methoxy-1-phenyl-indan-1-ol and100 mg of p-toluenesulfonic acid and the mixture was placed on a Rotovap® and the solvent was distilled in vacuo (40 mm) until an oil residue was obtained. The oil was chromatographed (silica, 1:1 hexane/methylene chloride followed by ether) to afford 8.6 g (60.2%) of 1-phenyl-4-methoxy-indene as a pale red oil.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)OB([C:35]2[CH:40]=[CH:39][C:38]([N:41]3[C:45](=[O:46])[N:44]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[NH:43][NH:42]3)=[CH:37][CH:36]=2)OC1(C)C>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:35]3[CH:40]=[CH:39][C:38]([N:41]4[C:45](=[O:46])[N:44]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[N:43]=[N:42]4)=[CH:37][CH:36]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Reactant: CC1(C)OB(c2ccc(N3NNN(COCC[Si](C)(C)C)C3=O)cc2)OC1(C)C
Product: C[Si](C)(C)CCOCn1nnn(-c2ccc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)cc2)c1=O
Yield: 31.6 %

Procedure:
Compound 3a (500 mg, 1.15 mmol) was subjected to Suzuki coupling conditions with 1-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-[[2-(trimethylsilyl)ethoxy]methyl]-1,2,3,4-tetrazolidin-5-one (1.44 g, 3.45 mmol) using the reaction conditions described in Example 1, Step G to obtain compound 14d as a white solid (236 mg, 31% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C34H39N9O3Si: 650.3 (M+H). Found 650.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[Sn].Cl.[OH-].[Na+]>O>[NH2:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Br)cc1N
Temperature: 100 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
4-Bromo-2-nitrotoluene (13.5 g, 62.5 mmol) and granulated tin (11.25 g, 95 mmol) were placed in a round bottomed flask to which concentrated hydrochloric acid (25 ml) was added in small (ca 5 ml) aliquots. A gentle reaction was evident during this addition period. When all the acid had been added the reaction mixture was heated and stirred at about 100° C. for 4 h. The solution was allowed to cool and a solution of sodium hydroxide (18.75 g) in water (32 ml) was added. The solution was heated at 100° C. for 1 h. After cooling, water (200 ml) was added and the solution was filtered. The aqueous filtrate was extracted with diethyl ether (200 ml). The filtered salts were also extracted with diethyl ether (200 ml). The combined organic layers were dried, filtered and evaporated to leave an oil. This was purified by distillation (112° C. at 4 mm Hg) to leave the title compound (6.76 g, 58%).
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[CH:7]=[C:8](N)[CH:9]=[CH:10][C:11]=1[F:12].Cl.[I-:15].[K+]>O>[Br:5][C:6]1[CH:7]=[C:8]([I:15])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: [I-]
Reactant: Nc1ccc(F)c(Br)c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Fc1ccc(I)cc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
Add at 0° C. a solution of sodium nitrite (2.0 g, 28.9 mmol) in water (15 mL) to a suspension of 3-bromo-4-fluorophenylamine (5.0 g, 26.3 mmol) in a 6 N aqueous solution of hydrochloric acid (25 mL) at 0° C. slowly over 10 min. Stir the mixture at 0° C. for 5 min. Add this solution to a solution of potassium iodide (4.37 g, 26.3 mmol) in water (125 mL) via syringe at 0° C. under nitrogen over 15 min. Stir at 0° C. for 30 min. Warm to room temperature. Extract with four times with dichloromethane (100 mL), dry (sodium sulfate), filter, and concentrate. Purify by silica gel chromatography, eluting with 100:0 to 95:5 hexanes:ethyl acetate to give the title compound as a colorless oil (5.83 g, 74%).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH3:12][C:13]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH2:16][CH2:17][N:18]1[C@H:23]2[CH2:24][CH2:25][C@@H:19]1[CH2:20][CH:21]([N:26]1[C:30]([CH:31]([CH3:33])[CH3:32])=[N:29][N:28]=[C:27]1[CH3:34])[CH2:22]2)[CH2:14][NH2:15]>>[F:11][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]([NH:15][CH2:14][C:13]([CH3:12])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:16][CH2:17][N:18]2[C@H:23]3[CH2:24][CH2:25][C@@H:19]2[CH2:20][CH:21]([N:26]2[C:30]([CH:31]([CH3:33])[CH3:32])=[N:29][N:28]=[C:27]2[CH3:34])[CH2:22]3)=[O:10])[CH2:6][CH2:7]1
Reactant: Cc1nnc(C(C)C)n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CN)c1ccccc1
Reactant: O=C(O)C1CCC(F)(F)CC1
Product: Cc1nnc(C(C)C)n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CNC(=O)C1CCC(F)(F)CC1)c1ccccc1

Procedure:
The title compound was synthesized by coupling 4,4-difluorocyclohexanecarboxylic acid and (2-methyl-4-{(1R,5S)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl}-2-phenylbutyl)amine (intermediate 24) as described in example 21.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CNCc1ccc(OC)cc1
Product: COc1ccc(CN(C)c2nc(Cl)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and N-methyl-4-methoxybenzylamine (45 mg, 0.302 mmol) by a procedure similar to example 1b and was isolated as white powder (30 mg, 60%). 1H NMR (CDCl3): 7.93 (dd, J=8.4 and 1.2 Hz, 1H), 7.78 (dd, J=8.4 and 1.5 Hz, 1H), 7.68 (ddd, J=8.4, 7.5 and 1.5 Hz, 1H), 7.34-7.26 (m, 3H), 6.96-6.92 (m, 2H), 4.94 (s, 2H), 3.83 (s, 3H), 3.31 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[OH:20][CH:21]1[CH:28]2[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:30][CH:22]1[CH:23]3[CH2:31][C:32](O)=[O:33])[CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:20][CH:21]1[CH:28]2[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:30][CH:22]1[CH:23]3[CH2:31][C:32]([N:12]1[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]1)=[O:33])[CH2:27]2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1C2CC3CC(C2)C(O)C1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CC4CC(C3)C(O)C1C4)C2
Reaction time: 0.5 h

Procedure:
Triethylamine 0.23 ml was added to a methylene chloride 5 ml solution of (IS)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.26 g and stirred at O@C for 30 min. 4-hydroxy-2-adamantyl acetic acid 0.26 g and WSC 0.31 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 25 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(4-hydroxy-2-adamantylacetyl)1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 25 ml solution of lithium aluminum hydride 70.5 mg and refluxed under heating for 1.5 hours. The reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform methanol=150:1) to obtain the product.
Reaction SMILES: C([N:8]1[CH2:18][CH2:17][N:16]2[C@@H:10]([CH2:11][CH2:12][O:13][C:14]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:15]=32)[CH2:9]1)C1C=CC=CC=1>C(O)C(F)(F)F>[CH3:23][C:22]1[C:14]2[O:13][CH2:12][CH2:11][C@H:10]3[CH2:9][NH:8][CH2:18][CH2:17][N:16]3[C:15]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc2c1OCC[C@H]1CN(Cc3ccccc3)CCN21
Solvent: OCC(F)(F)F
Product: Cc1cccc2c1OCC[C@H]1CNCCN21
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a solution of Example 226B (923 mg, 2.99 mmol) in trifluoroethanol (20 mL) was added Pd(OH)2—C (20%, wet, 185 mg, 1.3 mmol). The reaction mixture was stirred under H2 (30 psi) at 50° C. for 90 minutes after which the mixture was filtered through a nylon membrane. The solution was concentrated and purified via flash chromatography (0-30% methanol/dichloromethane) to afford the title compound 1H NMR (300 MHz, DMSO-d6) δ ppm 6.67-6.85 (m, 3H), 4.22-4.39 (m, 1H), 4.04-4.18 (m, 1H), 2.55-3.03 (m, 7H), 2.09 (s, 3H), 1.80-1.95 (m, 1H); MS (ESI+) m/z 219 (M+H)+.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([S:12][CH3:13])[N:5]=1.[C:14]([O:19][CH3:20])(=[O:18])[CH:15]([CH3:17])[OH:16].CN(C)C=O>O>[CH3:11][O:10][C:8]1[N:7]=[C:6]([S:12][CH3:13])[N:5]=[C:4]([O:16][CH:15]([C:14]([O:19][CH3:20])=[O:18])[CH3:17])[CH:9]=1
Reactant: COC(=O)C(C)O
Reactant: COc1cc(Cl)nc(SC)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(OC)nc(SC)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
0.4 g of sodium hydride was added to a mixture of 1.59 g of 4-chloro-6-methoxy-2-methylthiopyrimidine, 1.13 g of methyl lactate and 10 ml of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 5 hours, then, the reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.5 g of 6-methoxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylthiopyrimidine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[C:17]1([C:11]2([C:14]([OH:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C1(c2ccccc2)CCNCC1
Yield: 109.3 %

Procedure:
1-(tert-Butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (1.0 g, 3.3 mmol) was treated with 4 N HCl in dioxane (20 mL) for 2 hours at room temperature. The product was isolated by filtration to provide the title compound (0.74 g, 93%) as a white solid. MS (ES+) [M+H]+=206.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:23][C:24](=[O:33])[CH2:25][S:26][C:27]1[S:31][C:30]([NH2:32])=[N:29][CH:28]=1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:33])[CH2:25][S:26][C:27]1[S:31][C:30]([NH:32][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:29][CH:28]=1)[CH3:22]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1

Procedure:
{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester was prepared from 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid and (2-aminothiazol-5-ylsulfanyl)-acetic acid ethyl ester as described in Example 1. 1H-NMR (CDCl3): δ 11.78 (broad s, 1H), 7.88 (d, 2H), 7.57 (d, 2H), 7.54 (s, 1H), 4.18 (q, 2H), 3.80 (t, 1H), 3.46 (s, 2H), 3.05 (s, 3H), 2.31-2.23 (m, 1H), 1.92-1.85 (m, 1H), 1.80-1.40 (m, 7H), 1.26 (t, 3H), 1.12 (m, 2H); HPLC-MS: m/z=497 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: O[C@H]1CCNC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CC[C@H](O)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3S)-pyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (dd, J=7.83, 1.26 Hz, 1 H), 7.80-7.72 (m, 2 H), 7.54 (td, J=7.52, 1.39 Hz, 1 H), 7.43 (d, J=8.59 Hz, 1 H), 7.34 (td, J=7.71, 1.01 Hz, 1 H), 7.23 (dd, J=8.59, 1.77 Hz, 1 H), 6.05 (s, 1 H), 5.06 (s, 2 H), 4.55-4.43 (m, 1 H), 3.84 (dd, J=10.48, 4.42 Hz, 2 H), 3.58-3.43 (m, 4 H), 3.35 (s, 2 H), 2.35 (s, 3 H), 2.11 (dd, J=8.84, 4.55 Hz, 1 H), 2.06-1.97 (m, 1 H).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CN1CCOCC1.[CH3:46][O:47][C:48]([NH:50][C@H:51]([C:56](O)=[O:57])[C@H:52]([CH2:54][CH3:55])[CH3:53])=[O:49].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:38][C:56](=[O:57])[C@H:51]([C@H:52]([CH2:54][CH3:55])[CH3:53])[NH:50][C:48]([O:47][CH3:46])=[O:49])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:34])([CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere, 292 mg of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane (Example 2d) and 165 μl (1.5 mmol) of NMM in 4.8 ml of DMF are added to 113 mg of N-methoxycarbonyl-(L)-iso-leucine and 149 mg (0.50 mmol) of TPTU in 2.5 ml of DMF, and the midure is stirred at room temperature for 14 hours and worked up analogously to Example 3, yielding the title compound: m.p: 139-141° C.; TLC: Rf=0.7 (methylene chloride/methanol 10:1); HPLC20-100: tRet=14.6; FAB MS (M+H)+=711.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[C:10]=1[N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:12]1.O1C2C=CC=C(N3CC[C@H](N)C3)C=2CC1.[Cl:35]N1C(=O)CCC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:35])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[C:10]=1[N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:12]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)N[C@H]1CCN(c2c(Cl)ccc3c2CCO3)C1
Agent: N[C@H]1CCN(c2cccc3c2CCO3)C1
Product: CC(=O)N[C@H]1CCN(c2c(Cl)cc(Cl)c3c2CCO3)C1

Procedure:
The crude product isolated in Example 34 from the reaction of (S)-N-(2,3-dihydrobenzofuran-4-yl)-3-(amino)pyrrolidine (0.1 mmol) and N-chlorosuccinimide (0.11 mmol) was purified by preparative HPLC and the minor product of the reaction was isolated to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[C:17](=O)[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:24]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:24]=1
Reactant: Cc1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1c[nH]c(=O)[nH]c1=S

Procedure:
The product from step (iv) (1.35 g) and Lawesson's reagent (1.85 g) were heated at reflux in dioxane (50 ml) under nitrogen for 16 h. The reaction mixture was partitioned between ethyl acetate and brine. The organic phase was collected, dried (MgSO4), and evaporated under reduced pressure to leave a brown solid. The solid was triturated with ethyl acetate and filtered to leave a yellow solid.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:8]1[CH:9]=[C:10]([C:18]([O:20]C)=[O:19])[C:11]([C:14](OC)=O)=[N:12][CH:13]=1.[NH2:22][C:23]([CH3:30])([CH:27]([CH3:29])[CH3:28])[C:24]([NH2:26])=[O:25].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.O>[O:3]1[CH2:4][CH2:5][CH2:6][CH2:7][O:1][CH:2]1[C:8]1[CH:13]=[N:12][C:11]([C:14]2[NH:26][C:24](=[O:25])[C:23]([CH:27]([CH3:29])[CH3:28])([CH3:30])[N:22]=2)=[C:10]([CH:9]=1)[C:18]([OH:20])=[O:19]
Reactant: COC(=O)c1cc(C2OCCCCO2)cnc1C(=O)OC
Reactant: CC(C)C(C)(N)C(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C1(C)N=C(c2ncc(C3OCCCCO3)cc2C(=O)O)NC1=O
Temperature: 25 °C
Yield: 57.2 %

Procedure:
5-(1,3-Dioxepan-2-yl)-2,3-pyridinedicarboxylic acid, dimethyl ester (0.9 g, 0.00305 mol) in toluene is added to 2-amino-2,3-dimethylbutyramide (0.4 g, 0.00305 mol) and potassium tert-butoxide (0.69 g, 0.0061 mol) in toluene. The mixture is heated for 3 hours from 60° to 70° C. The reaction mixture is cooled to room temperature, water is added and the mixture is concentrated in vacuo to give an oil. The oil is diluted with water and washed with ether. The aqueous solution is acidified to pH 3.1 with 2 normal hydrochloric acid solution and extracted with methylene chloride. The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (0.63 g, 57%) mp 60°-69° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:10]=[C:9]([C:11](Cl)=[O:12])[NH:8][C:7]=1[C:14]([O:16][CH3:17])=[O:15]>C1COCC1>[Cl:5][C:6]1[CH:10]=[C:9]([C:11]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:12])[NH:8][C:7]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NC1CC1
Reactant: COC(=O)c1[nH]c(C(=O)Cl)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c(C(=O)NC2CC2)cc1Cl
Yield: 70.3 %

Procedure:
Cycloproplyamine (0.166 g, 2.90 mmol) was added to a solution of methyl 3-chloro-5-(chlorocarbonyl)-1H-pyrrole-2-carboxylate (0.150 g, 0.580 mmol) in THF and the resulting solution stirred until no starting material was evident by TLC. The solvent was evaporated and purification was accomplished by silica gel column chromatography (30-100% EtOAc/hexanes) to afford the title compound (0.099 g, 70%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 10.81 (br. s., 1H), 7.71 (br. s., 1H), 6.78 (s, 1H), 3.84 (s, 3H), 2.79-2.92 (m, 1H), 0.73 (d, 2H), 0.57 (d, 2 H) LCMS: m/z 243.1 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:7]=1[C:8](N(OC)C)=[O:9])[CH2:2][CH2:3][CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOC(C)=O>[CH2:1]([O:5][C:6]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:7]=1[CH:8]=[O:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCCCOc1cc(C(F)(F)F)ccc1C=O
Yield: 63.6 %

Procedure:
2-Butoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (825 mg) was reacted with 1 M LAH (31 ml) at −50° C. for 1 hour as described above to yield title compound (423 mg) after column chromatography (Hex/EtOAc=20/1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].CI.[C:13](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 100 %

Procedure:
Step AH (1): To a solution of 2-bromo-5-hydroxybenzaldehyde (1000.0 mg, 4.975 mmol) in DMF (20 mL) were added methyl iodide (0.31 mL, 5.000 mmol) and potassium carbonate (1036.6 mg, 7.500 mmol). The reaction mixture was stirred at rt for 2.5 days. Water was added and the reaction mixture was extracted with hexanes-ether (1:1) solvent system. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum to yield 2-bromo-5-methoxybenzaldehyde (1069.8 mg, 100%) as colorless oil. LC-MS (M+H)+=215.11. 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H). 7.70 (d, J=10 Hz, 1H) 7.35 (d, J=3 Hz, 1H) 7.23 (dt, J1=7.0 Hz, J2=2.0 Hz, 1H) 3.83 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH3:16][O:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH3:29]>C(O)(=O)C>[CH3:16][O:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:11]([C:6]2[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=2[C:8]([OH:10])=[O:9])=[O:12])=[C:21]1[CH3:29]
Reactant: COCCn1c(C)cc2ccccc21
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: CC(=O)O
Product: COCCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Yield: 112 %

Procedure:
Proceeding in a manner similar to that described in part A of Example 8 above, 30.0 g of tetrachlorophthalic anhydride was interacted with 40.0 g of 1-(2-methoxyethyl)-2-methylindole in 75.0 ml of glacial acetic acid at approximately 110° C. for approximately one hour to obtain 55.83 g of 2-[1-(2-methoxyethyl)-2-methylindol-3-yl]carbonyl-3,4,5,6-tetrachlorobenzoic acid, (Formula V: R=CH3OC2H4 ; R1 =CH3 ; X=Cl4 ; Y=H), a pale yellow solid which melted at 182°-184° C. A significant infrared maximum appeared at 1750 (C=O; s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:8][C:7]1[C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1Cl
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(-c2cn3cccc(Cl)c3n2)cc1
Yield: 80.3 %

Procedure:
To a solution of 2-amino-3-chloropyridine (6.51 g, 51 mmol) and 2-bromo-4′-fluoroacetophenone (13.0 g, 60 mmol) in ethanol (100 mL) was added sodium bicarbonate (4.91 g, 60 mmol) and the reaction mixture was heated at reflux for 6 hours. The resulting mixture was concentrated to a solid in vacuo. This residue was dissolved in ethyl acetate and the organic phase was washed with water and an aqueous sodium chloride solution. The organic phase was dried (magnesium sulfate), filtered through a silica gel pad and concentrated to give a solid. This solid was recrystallized from acetonitrile, to give 10.1 g (80%) 8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridine as a solid. 1H NMR (CDCl3): δ 8.06 (d, 1H), 7.96 (q, 2H), 7.86 (s, 1H), 7.25 (d, 1H), 7.13 (t, 2H), 6.73 (t, 1H); 19F NMR (CDCl3) δ −114.0; MS m/z 247 (M+1).