Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)=[CH2:2].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1COCC1>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C1CNCCN1
Reactant: C=Cc1ccc(CCl)cc1
Solvent: C1CCOC1
Product: C=Cc1ccc(CN2CCNCC2)cc1
Yield: 81.2 %

Procedure:
Synthesized according to General Procedure A: 4-vinylbenzyl chloride (7, 5.56 g, 32.8 mmol, 1 equiv.), piperazine (16.9 g, 196.6 mmol, 6 equiv.), THF (71.8 mL). Purification with flash column chromatography on silica gel (gradient, 4:1 to 1:4 EtOAc:MeOH) afforded 8 (5.39 g, 81%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 7.32 (d, 2H, J=8.0 Hz), 7.24 (d, 2H, J=8.0 Hz), 6.66 (dd, 1H, J=11.0, 18.0 Hz), 5.69 (dd, 1H, J=0.5, 18.0 Hz), 5.18 (dd, 1H, J=0.5, 11.0 Hz), 3.43 (s, 2H), 2.84 (t, 4H, J=5.0 Hz), 2.63 (br s, 1H), 2.37 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 137.5, 136.4, 136.2, 129.1, 125.8, 113.3, 63.1, 54.0, 45.7.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[NH:15][CH3:16])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl.CCOC(C)=O.[Cl:25][C:26]1[CH:31]=[C:30](CCl)[CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:25][C:26]1[CH:31]=[C:30]([CH2:1][N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:17])[NH:15][CH3:16])[CH2:12][CH2:13]2)[CH:29]=[CH:28][N:27]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: CNC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
1-Boc-4-(N-methylcarbamoyl)piperazine was treated with 8 M HCl/EtOAc to afford a salt, then the salt (1.0 equiv) was mixed with 2-chloro-4-(chloromethyl)pyridine (1.0 equiv) (Preparation B-11) and K2CO3 (4 equiv) in DMF. The mixture was stirred for 1 h at rt. After removing most of the solvent, the residue was partitioned in water and EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid (˜90% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]3([OH:20])[CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:24]>CO>[NH2:24][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]3([OH:20])[CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: CCCc1nc2c(Cl)nc3ccccc3c2n1CC1(O)CCC1
Solvent: CO
Product: CCCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCC1
Temperature: 150 °C

Procedure:
1-[(4-Chloro-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol (1.56 g) was combined with a solution of ammonia in methanol (23 mL). The mixture was heated at 150° C. in a pressure vessel for 2 days. A portion of the solvent was removed under vacuum and then the mixture was diluted with additional methanol. A solid was isolated by filtration, washed with methanol, triturated with acetonitrile, and then dried. The material was suspended in water (70 mL). Concentrated hydrochloric acid (1.4 mL) was added and the mixture was heated at 90° C. for 30 minutes. The hot solution was neutralized with solid sodium bicarbonate. The solution was allowed to cool to ambient temperature. A precipitate was isolated by filtration, washed well with water, and then dried to provide 1-[(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol as a white powder, mp 228.0-229.0° C. Anal. Calcd for C18H22N4O C, 69.65; H, 7.14; N, 18.05. Found: C, 69.36; H, 7.24; N, 18.03.
Reaction SMILES: C(OC([N:6]1[CH:10]=[C:9]([C:11]2[C:12]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:8]=[N:7]1)C)C.O1CCCC1.Cl.[OH-].[Na+]>O>[NH:6]1[CH:10]=[C:9]([C:11]2[C:12]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:8]=[N:7]1
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88 %

Procedure:
To a reactor equipped with overhead stirring, condenser, thermowell, and nitrogen inlet was charged crude 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (15, 1030.9 g based on 100% conversion, 2.66 mol), tetrahydrofuran (THF, 0.9 L), water (H2O, 4.4 L), and a 10% aqueous HCl solution (2.7 L, 10.64 mol, 3.44 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 2-5 h. When the reaction was deemed complete by HPLC analysis, the reaction mixture was treated with a 30% aqueous sodium hydroxide (NaOH) solution (940 mL, 11.70 mol, 3.78 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1-2 h. The solids were collected by filtration, washed with water (2×0.75 L), and dried in a vacuum oven at 45-55° C. to constant weight to afford the crude 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 826.8 g, 839.1 g theoretical, 98.5% yield) as off-white solids (94.2 area % pure by HPLC). This crude material was subsequently recrystallized in acetonitrile to afford pure compound 5 (738.4 g, 839.1 g theoretical, 88% yield) as white crystals (99.5 area % by HPLC), which was found to be identical in every comparable aspect to the material made from Method A.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:23][C:24]1([NH2:28])[CH2:27][O:26][CH2:25]1>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:28][C:24]3([CH3:23])[CH2:27][O:26][CH2:25]3)=[O:18])=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(CO)c1COc1ccc(C(=O)O)cn1
Reactant: CC1(N)COC1
Product: CCCCc1noc(CO)c1COc1ccc(C(=O)NC2(C)COC2)cn1
Yield: 48 %

Procedure:
As described in example 52g, 6-[3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (49 mg, 0.16 mmol) was converted, using 3-methyl 3-oxetanamine instead of cyclobutylamine, to the title compound (29 mg, 48%) which was obtained as a colorless oil. MS: m/e=376.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH3:18])[C@H:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][NH:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[C:1]([O:5][C:6](=[O:19])[N:7]([CH3:18])[C@H:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][N:10]([CH3:11])[S:28]([CH3:27])(=[O:30])=[O:29])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC[C@@H](Cc1cccs1)N(C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Temperature: -78 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
N-Methyl-N-((1R)-2-methylamino-1-((2-thienyl)methyl)ethyl)carbamic acid tert-butyl ester (1.72 g, 6.05 mmol) was dissolved in dichloromethane (30 ml). Triethylamine (0.84 ml, 6.05 mmol) was added. The solution was cooled to −78° C. Methanesulfonyl chloride (0.47 ml, 6.05 mmol) was added dropwise. The reaction mixture was warmed to room temperature over a period of 3.5 h. It was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (100 ml). It was washed with 10% aqueous sodium hydrogen sulfate solution (200 ml). The aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (180 g), using ethyl acetatelheptane 1:1 as eluent, to give 1.94 g of N-methyl-N-((1R)-2-(N-methyl-N-(methylsulfonyl)amino)-1-((2-thienyl)methyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[C:18]([CH3:19])=[C:17](Cl)[N:16]=[CH:15][N:14]=1.ClC1C(C)=C(C2C=CC(C(F)(F)F)=CC=2)N=CN=1>>[Cl:12][C:13]1[C:18]([CH3:19])=[C:17]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(Cl)ncnc1Cl
Agent: Cc1c(Cl)ncnc1-c1ccc(C(F)(F)F)cc1
Product: COc1ccc(-c2ncnc(Cl)c2C)cc1

Procedure:
Prepared from 4-methoxyphenylboronic acid (0.93 g, 6.13 mmol) and 4,6-dichloro-5-methylpyrimidine using the procedure described for Intermediate 62.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25]NCCC)=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:32]([NH2:37])[CH2:33][CH:34]([CH3:36])[CH3:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][NH:37][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:23][CH:24]=3)=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: CCCNCc1ccc(CNCCOc2ccc(C#Cc3ccc(Cl)cc3)cc2)cc1
Reactant: CC(C)CCN
Product: CC(C)CCNCc1ccc(CNCCOc2ccc(C#Cc3ccc(Cl)cc3)cc2)cc1

Procedure:
Compound 5 was synthesized using the procedure described for Compound 2 except that isoamylamine was used in the final reductive amination step. Compound 5 was obtained as a white solid. MS 462; 1H NMR (CDCl3) δ 4.10 (t, 2H), 3.86 (s, 2H), 3.77 (s, 2H), 3.03 (t, 2H), 2.63 (t, 2H), 0.89 (d, 6H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[N:42]1([CH2:47][CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:64]=[CH:63][C:62]([NH2:65])=[CH:61][N:60]=3)=[CH:54][N:53]=2)=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl>[N:42]1([CH2:47][CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:60]=[CH:61][C:62]([NH:65][C:14](=[O:16])[C:13]4[CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]5[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:1])([F:23])[F:22])[CH:4]=5)[CH:10]=[CH:11][C:12]=4[CH3:18])=[CH:63][N:64]=3)=[CH:54][N:53]=2)=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: Nc1cnc(Nc2ccc(C(=O)NCCN3CCCC3)nc2)nc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)O
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)Nc1cnc(Nc2ccc(C(=O)NCCN3CCCC3)nc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
Intermediate 3 (Example 5) (0.070 g, 0.215 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.046 g, 0.26 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.05 mL, 0.43 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 23 (Example 31) (0.074 g, 0.226 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.027 g, 20%).
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[C:12]([C:16]1[CH:41]=[CH:40][C:19]([O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[C:26]([C:37](Cl)=[O:38])[N:27]=[C:28]3[CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:41]=[CH:40][C:19]([O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[C:26]([C:37]([NH:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:2])=[O:11])=[O:38])[N:27]=[C:28]3[CH2:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)c1ccccc1N
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)Cl)nc(CC4CCCC4)c3c2)cc1
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)Nc4ccccc4C(=O)O)nc(CC4CCCC4)c3c2)cc1
Yield: 57.4 %

Procedure:
The title compound (30 mg) was prepared following the same procedures that was described for example 432 from methyl-2-aminobenzoate (0.1 mmol, 15.1 mg) and 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl chloride (46 mg, 0.1 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Br[CH2:13][CH2:14][CH3:15]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:13][CH2:14][CH3:15])[N:6]=[C:5]2[I:11]
Reactant: CCCBr
Reactant: Clc1ccc2[nH]nc(I)c2c1
Product: CCCn1nc(I)c2cc(Cl)ccc21
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield from 5-chloro-3-iodo-indazole and 1-bromopropane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.92 (3H, t, J=7.6 Hz), 1.91-1.97 (2H, m), 4.33 (2H, t, J=7.2 Hz), 7.31 (1H, d, J=8.8 Hz), 7.37 (1H, dd, J=2.0, 8.8 Hz), 7.46 (1H, d, J=1.2 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:7]=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>N1C=CC=CC=1>[CH2:32]([O:31][C:29](=[O:30])[NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:15]=2)[N:7]=1)[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Solvent: c1ccncc1
Product: CCOC(=O)NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.6 %

Procedure:
To a solution of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl)amino)phenyl)-1-pyrrolidinecarboxamide (150 mg, 0.30 mmol) in pyridine (5 mL) was added ethyl chloroformate (38.5 mg, 0.35 mmol) at 0° C. under N2. The resulting reaction mixture was stirred at 0° C. for 1 h and then was stirred at room temperature overnight. The mixture was washed with water (3×50 mL). Then the reaction mixture was concentrated. Purification by HPLC chromatography using acetonitrile/water gave the title compound (10 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=[O:12])[C@@:5]1([CH3:27])[C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([CH:24]([CH3:26])[CH3:25])[CH:16]=1.COC[C@H]1[C@@H](/C=C/C(/C)=C/C(OCC)=O)[C@]1(C)C1C=C(C(C)C)C=C(C(C)C)C=1>>[CH3:1][O:2][CH2:3][C@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=[O:12])[C@:5]1([CH3:27])[C:15]1[CH:16]=[C:17]([CH:24]([CH3:25])[CH3:26])[CH:18]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=1
Reactant: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: CCOC(=O)/C=C(C)/C=C/[C@@H]1[C@H](COC)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: COC[C@H]1[C@@H](/C=C/C(C)=C/C(=O)O)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 73 %

Procedure:
Following a procedure similar to that for the preparation of Compound 28 but using Compound 25 as the starting material afforded the title compound (10 mg, 73% yield) as a white solid:
Reaction SMILES: C([CH:18]1[CH:21]([NH:22][C@H:23]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[C:24]([NH:26][N:27]2[CH2:31][CH2:30][C@H:29]([N:32]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:28]2)=[O:25])[CH2:20][N:19]1[CH3:52])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>N1CCCCC1.CN(C=O)C>[CH3:52][N:19]1[CH2:20][CH:21]([NH:22][C@H:23]([CH2:44][C:45]2[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=2)[C:24]([NH:26][N:27]2[CH2:31][CH2:30][C@H:29]([N:32]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:28]2)=[O:25])[CH2:18]1
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC2CN(C)C2C(=O)OCC2c3ccccc3-c3ccccc32)C1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC2CN(C)C2)C1
Reaction time: 0.5 h
Yield: 10.3 %

Procedure:
(2R)-2-{Fmoc[1-(methyl)azetidine-3-yl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step D (71.1 mg, 1 mmol) was dissolved in 50% of piperidine-DMF (2 mL). After being stirred 30 min., the reaction mixture was concentrated in vacuo, and the residue was purified by HPLC to give the title compound (52 mg, 73.5%).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].C1(C(C2CCCCC2)[C:41](N[C@@H]2[C@H]3[C@H](CNC3)CC2)=[O:42])CCCCC1>>[CH3:41][O:42][C:4]1[CH:3]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:24]1[CH2:25][C@@H:26]2[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:14]([CH3:33])[CH3:13])[CH2:20][CH2:21][C@@H:22]2[CH2:23]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: COc1ccccc1CN1C[C@H]2CC[C@H](NC(=O)C(c3ccccc3)C(C)C)[C@H]2C1

Procedure:
The title compound was prepared by substituting 2-methoxybenzaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.50 (t, J=7.3, 1H), 7.62 (d, J=7.3, 2H), 7.55 (d, J=7.8, 1H), 7.32 (dq, J=3.8, 11.6, 2H), 7.25 (dd, J=3.6, 7.5, 2H), 7.04 (dt, J=7.4, 11.4, 1H), 6.89 (t, J=8.3, 1H), 4.43-4.31 (m, 1H), 3.80-3.57 (m, 5H), 3.21 (d, J=10.4, 1H), 2.99 (d, J=6.2, 0.5H), 2.61 (ddd, J=4.5, 12.6, 15.9, 2.5H), 2.52-2.45 (m, 0.5H), 2.45-2.31 (m, 3.5H), 2.19-2.09 (m, 0.5H), 2.00-1.80 (m, 1H), 1.72 (ddd, J=6.5, 12.3, 19.3, 1H), 1.47-1.25 (m, 2.5H), 1.20 (dd, J=3.0, 6.4, 3H), 0.70 (d, J=6.7, 3H); MS (ESI+) m/z 407 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=[C:3]1[C:19]([OH:21])=O>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2[CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][C:17]=3[C:19](=[O:21])[C:3]1=2
Reactant: Cc1cccc(OCc2cc(C(=O)O)n(C)c2C(=O)O)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc2c(c1)OCc1cc(C(=O)O)n(C)c1C2=O
Reaction time: 0.5 h

Procedure:
To a stirred ice-bath cooled portion of trifluoroacetic anhydride (30 ml) was added 1-methyl-3-[(m-methylphenoxy)methyl]pyrrole-2,5-dicarboxylic acid (1.0 g) all at once, the mixture stirred 0.5 hour, the ice-bath removed, and the reaction mixture stirred at room temperature. After ca. 3 hours, trifluoroacetic acid (35 ml) was added, and the mixture allowed to stir at ambient temperature. After three hours the reaction mixture was added to excess stirred ice-water, the aged mixture filtered, washed well with water and dried to give crude 4,10-dihydro-1,7-dimethyl-10-oxo-1H[1]-benzoxepino[4,3-b]pyrrole-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].[CH2:22]=O.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(O)(=O)C>[O:27]1[CH2:28][CH2:29][N:24]([CH2:22][C:21]2[N:9]3[CH:10]=[C:11]([S:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:13][C:8]3=[N:7][C:6]=2[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:25][CH2:26]1
Reactant: C1COCCN1
Reactant: C=O
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccc(Sc3ccccc3)cn2c1CN1CCOCC1

Procedure:
From the reaction of 0.75 g. of 2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine and 0.83 ml. acetic acid, 18 ml. of 37% formaldehyde and 0.216 g. of morpholine, following the procedure of Example 8, there is obtained 3-(morpholinomethyl)-2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine m.p. 158°-182° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][CH2:38]O)=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:61]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][CH2:38][Br:61])=[CH:6][CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1ccc(OCCc2c(CCCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCc2c(CCCBr)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
104.0 mg of 4-{2-[1-Benzhydryl-5-chloro-2-(3-hydroxy-propyl)-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (0.0002M, 1.0 eq.) was dissolved in 2.0 mL of anhydrous methylene chloride. To the solution 116.0 mg of polystyrene bound triphenylphosphine was added (1.61 mmol/g, 0.0002M, 1.0 eq.) followed by 125.0 mg of carbon tetrabromide (0.0004M, 2 eq.). The suspension was stirred for 2 hrs at room temperature at which point the reaction was filtered and the filtrate evaporated to an orange oil. The oil was purified via column chromatography with ethyl acetate/hexanes (2:98) to give 100 mg (86%) of 4-{2-[1-Benzhydryl-2-(3-bromo-propyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester title as a yellow foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]([CH3:28])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:30](B1C2CCCC1CCC2)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.O1CCOCC1>[C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]([CH3:28])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:15]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: CC(C(=O)Nc1ccc(Br)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CC(C(=O)Nc1ccc(Cc2ccccc2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-bromo-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate C2a (50 mg, 0.11 mmol), 9-benzyl-9-borabicyclo[3.3.1]-nonane (283 μl, 0.14 mmol) Cs2CO3 (71 mg, 0.22 mmol), 1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (8.0 mg, 0.01 mmol) and dioxane (0.6 ml) is stirred under argon atmosphere for 45 minutes at 70° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 26 mg (51%). HPLC-MS: M+H=470; tR=1.97 min (*Method—4).