Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6](Cl)=[O:7].[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:7]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1F
Reactant: CS(N)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(C)(=O)=O)cc1F

Procedure:
A solution of 25.2 g. of 3-fluoro-4-(hexadecylamino)-benzoyl chloride hydrochloride and 5.6 g. of methanesulfonamide in 250 ml of pyridine is stirred under reflux for 2 hours and then concentrated in vacuo. The residue is partitioned between water and diethyl ether; the aqueous layer acidified with 1 N HCl, and the organic layer separated, dried (MgSO4), and evaporated. Crystallization of the residual white solid from 60% aqueous acetic acid and then from methylene chloride-hexane affords N-[3-fluoro-4-(hexadecylamino)benzoyl]methanesulfonamide as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])[CH:23]=2)[C:10]=1[CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])C.[OH-].[Na+]>>[C:41]([CH2:40][CH2:39][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([S:33]([CH2:36][CH2:37][CH3:38])(=[O:34])=[O:35])[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:46])=[O:3])([OH:43])=[O:42]
Reactant: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)cc(-c2ccsc2)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1
Yield: 92.6 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-(propane-1-sulfonyl)-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy]-butyric acid ethyl ester (144 mg, 0.21 mmol) and 1.0 N aqueous sodium hydroxide (2.1 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(3-(propane-1-sulfonyl)-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy]-butyric acid (120 mg, 91%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C32H40O8S2 (M+Na)+ 639.2057, found 639.2056.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[O:37])=[CH:34][CH:35]=2)[N:10]=[CH:9]1
Reactant: O=C(c1ccc(O)cc1)C1CCCCC1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: O=C(c1ccc(OCCCc2c[nH]cn2)cc1)C1CCCCC1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of cyclohexyl 4-hydroxyphenyl ketone are treated as described in Example 76.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([O:21]CC)=[O:20])[O:16]2)=[CH:11][CH:10]=1.I[CH3:33]>>[Cl:1][C:2]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:29])[CH3:30])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH3:33])([C:19]([OH:21])=[O:20])[O:16]2)=[CH:11][CH:10]=1
Reactant: CI
Reactant: CCOC(=O)C1CCc2ccc(OCCCOc3ccc(C(C)(C)C)cc3Cl)cc2O1
Product: CC1(C(=O)O)CCc2ccc(OCCCOc3ccc(C(C)(C)C)cc3Cl)cc2O1

Procedure:
The title compound was prepared from ethyl 7-(3-(2-chloro-4-tert-butylphenoxy)propoxy)-chromane-2-carboxylate following the procedures described in Example 1, Step C employing iodomethane instead of iodoethane, followed by hydrolysis as described in Example 1, Step G.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@:7]([OH:26])([CH:8]=[CH:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:25][C@@H:13]3[C:14]2=[O:24])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)C>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@:7]([OH:26])([CH:8]=[CH:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:25][C@@H:13]3[C:14]2=[O:24])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3C=C[C@]2(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](C=C[C@]4(O)C[C@@H](O)CC[C@]34C)[C@@H]1[C@@H]1C[C@@H]1C2=O

Procedure:
A solution of 3β-acetoxy-5-hydroxy-15β,16β-methylene-5β-androst-6-en-17-one in 300 ml of methanol is stirred with 15 g of potassium carbonate for 30 minutes at room temperature. The reaction solution is diluted with diethyl ether, washed with water, dried, and evaporated, thus obtaining 27 g of 3β,5-dihydroxy-15β,16β-methylene-5β-androst-6-en-17-one, mp 187°-190° C., (acetone).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([C@@H:13]3[O:21][C@H:20]([CH2:22][O:23]C(=O)C4C=CC=CC=4)[C@@H:19]([CH3:32])[C@H:14]3[O:15]C(=O)C)[C:4]=2[N:5]=[CH:6][N:7]=1.N.[OH:34]O>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]([NH2:12])=[O:34])=[CH:9][N:8]([C@@H:13]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([CH3:32])[C@H:14]3[OH:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OO
Reactant: CC(=O)O[C@@H]1[C@H](C)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cc(C#N)c2c(N)ncnc21
Agent: N
Product: C[C@H]1[C@@H](O)[C@H](n2cc(C(N)=O)c3c(N)ncnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound from Step B (51 mg, 0.12 mmol), ethanolic ammonia (5 mL, saturated at 0° C.), aqueous ammonia (5 mL, 30%) and aqueous hydrogen peroxide (1 mL, 35%) was stirred room temperature for 8 h. The solution was evaporated and:the residue purified on silica gel column with a solvent system of CH2Cl2/MeOH: 10/1 to give the title compound as a white solid (28 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]([OH:12])=O)[CH:4]=1.[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1>>[NH:15]1[C:14]([NH:13][C:10]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([CH3:9])[N:6]=2)=[O:12])=[N:18][N:17]=[N:16]1
Reactant: COc1cc(C)nc(C(=O)O)c1
Reactant: Nc1nnn[nH]1
Product: COc1cc(C)nc(C(=O)Nc2nnn[nH]2)c1
Yield: 73.2 %

Procedure:
0.8 g of 4-methoxy-6-methyl-2-pyridinecarboxylic acid, 0.82 g of N,N'-carbonyldiimidazole and 0.45 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.82 g of N-(5-tetrazolyl)-4-methoxy-6-methyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C[O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([F:28])[CH:22]=1)=[O:17]>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH:19]4[CH2:20][CH:18]4[C:16]([OH:17])=[O:15])=[CH:22][C:23]=3[F:28])[CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)C1CC1c1ccc(O)c(F)c1
Reactant: ClCc1cccc(SC2CCC2)n1
Product: O=C(O)C1CC1c1ccc(OCc2cccc(SC3CCC3)n2)c(F)c1
Yield: 71 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.018 g, 0.08 mmol) obtained in Step C of Preparation Example 37 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.018 g, 0.08 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.022 g, 71%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:46])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([NH:31][C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[O:33])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:41]([O:43]CC)=[O:42])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:46])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([NH:31][C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])=[O:33])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:41]([OH:43])=[O:42])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(NC(=O)OCC[Si](C)(C)C)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3cc(NC(=O)OCC[Si](C)(C)C)ccc3c12
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a homogeneous, burgundy solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)carbonylamino)-9H-pyrido[3,4-b]indole-1-carboxylate (0.565 g, 0.884 mmol) in tetrahydrofuran (30.2 mL) and methanol (10.05 mL) was added a solution of lithium hydroxide hydrate (0.148 g, 3.54 mmol) in water (4 mL). After 1 hr, the reaction was concentrated in vacuo, acidified with 1 N aqueous HCl to pH ˜5 by litmus paper. The precipitate was filtered, dried over Drierite to give the desired product (0.419 g, 0.686 mmol, 78% yield) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)=[CH:4][CH:3]=1.[CH:18]1([CH2:21][NH2:22])[CH2:20][CH2:19]1.[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:22][CH2:21][CH:18]2[CH2:20][CH2:19]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(OCc2ccc(Cl)cc2)c1
Reactant: NCC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Clc1ccc(COc2cccc(CNCC3CC3)c2)cc1
Reaction time: 1 h
Yield: 106.8 %

Procedure:
A solution of 62 g of 3-(4-chlorobenzyloxy)-benzaldehyde and 20 g of cyclopropylmethylamine in 750 ml of methanol was stirred at room temperature for 15 minutes. Thereto was slowly added 12 g of sodium borohydride with ice-cooling. The resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was dissolved in 1 liter of chloroform. The solution was washed with water, dried with anhydrous magnesium sulfate, and subjected to vacuum distillation to remove the solvent, whereby 81 g of 3-(4-chlorobenzyloxy)-N-cyclopropylmethylbenzylamine was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[Li][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].C(OCC)(=O)C.CCCCCC>C(OCC)C.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:9]=[CH:8]2
Reactant: [Li]c1ccccc1OC
Reactant: COc1cccc2cccnc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ccc2cccc(OC)c2n1
Reaction time: 2 h

Procedure:
A solution of 8-methoxyquinoline (5.54 g, 34.8 mmol, 1.0 eq) in 55 ml diethyl ether was slowly dropped (within about 30 min) into a solution of o-lithioanisole (4.37 g, 38.4 mmol, 1.1 eq) in 55 ml diethyl ether (each 55 mL). A yellow green fluorescing solution was formed. At the conclusion of the addition, stirring was continued at room temperature for a further 2 hours, after which no more educt could be detected by thin layer chromatography. During the reaction, the color of the reaction mixture changed from fluorescent yellow to green to green-brown. The reaction mixture was worked up by adding it to ice and subsequent extraction with diethyl ether (3×40 ml). The combined organic phases (yellow) were dried over MgSO4 and the solvent was removed in a rotary evaporator. The residue was dissolved in 200 ml dichloromethane and stirred with ca. 40 equivalents of activated manganese dioxide (Merck) until the thin layer chromatographic control (ethyl acetate/hexane=4/6) showed that all of the crude product had reacted. The manganese dioxide was filtered off and the solvent removed in the rotary evaporator. The product was dried under vacuum.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=2)([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[OH:44])=[CH:39][CH:38]=1.Cl[CH2:59][CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][C:66]([C:69](=[O:71])[CH3:70])=[CH:65][C:64]=1[O:72][CH3:73].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].C(O)(=O)C(O)=O>C(O)CCC>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:52]=[CH:53][C:54]([Cl:57])=[CH:55][CH:56]=2)([OH:44])[CH:45]2[CH2:46][CH2:47][N:48]([CH2:59][CH2:60][CH2:61][O:62][C:63]3[CH:68]=[CH:67][C:66]([C:69](=[O:71])[CH3:70])=[CH:65][C:64]=3[O:72][CH3:73])[CH2:49][CH2:50]2)=[CH:39][CH:38]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)C1CCNCC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1
Yield: 30 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 2.5 g (0.0075 mole) of α,α-bis(4-chlorophenyl)-4-piperidinemethanol, 1.8 g (0.0075 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a gummy solid as residue. This solid was converted to the oxalic acid salt and the solid was recrystallized from absolute ethanol to yield 1.4 g (30%) of title compound as a pale-yellow solid, mp 89°-113° C. with decomposition.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Br[CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].O>CN(C=O)C>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[CH2:17][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:7])=[CH:10][CH:11]=1)[CH3:21]
Reactant: CCOC(CBr)OCC
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(CO)cc1)OCC
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Caesium carbonate (39.4 g) was added to a solution of 4-hydroxymethyl-phenol (10 g) and 2-bromo-1,1-diethoxyethane (12.73 mL) in DMF (200 mL) and the resulting mixture stirred at 90° C. for 16 h. The reaction was poured into water (500 mL) and extracted with ethyl acetate (3×250 mL). The combined organic solutions were washed with water (250 mL) and brine (250 mL), then dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with an isohexane to diethyl ether gradient to give the subtitled compound as a yellow oil.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1.CO.C(Cl)Cl>CS(C)=O>[CH:23]1([NH:28][C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: ClCCl
Solvent: CO
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCCC1
Temperature: 100 °C
Yield: 20.2 %

Procedure:
Prepared according to Example 127 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 39.8 mg, 0.094 mmol) and cyclopentanamine (0.028 mL, 0.282 mmol) in DMSO (0.8 mL), heating at 100° C. for 50 min. Purification by reversed-phase HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% ACN/H2O+0.1% TFA) followed by chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-3% MeOH/DCM) furnished 2-(3-(cyclopentylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (6.8 mg, 0.019 mmol, 20% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (1H, br. s.), 7.89 (1H, d, J=7.4 Hz), 7.56 (1H, d, J=7.6 Hz), 7.32 (1H, t, J=7.8 Hz), 7.12 (1H, s), 6.94 (1H, d, J=5.9 Hz), 4.34-4.42 (1H, m), 4.03 (1H, s), 3.43 (2H, t, J=6.9 Hz), 2.87 (2H, t, J=6.8 Hz), 2.55 (3H, s), 2.04-2.17 (2H, m), 1.69-1.83 (4H, m), 1.66 (2H, d, J=7.6 Hz). m/z (ESI, +ve) 362.1 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:41]1([C:47](Cl)=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:41]1([C:47]([N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:26])=[O:25])=[CH:19][CH:18]=2)[C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:10][CH:11]=2)=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(CNc3ccc(OCCN4CCCC4)cc3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(CN(C(=O)C3CCCCC3)c3ccc(OCCN4CCCC4)cc3)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of toluene-4-sulfonic acid 4-{[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-methyl}-phenyl ester (0.120 g, 0.26 mmol) and triethylamine (0.18 mL, 1.36 mmol) in 2 mL methylene chloride was added cyclohexanecarbonyl chloride (0.138 mL, 1.03 mmol). The reaction mixture was stirred for 3 hr. at room temperature. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with an additional 2 mL of methylene chloride. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated. Flash filter chromatography afforded the title compound of Step A. MS 577.1 (M+1)+
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[N:10][CH:11]=1.[N+:22]([CH3:25])([O-:24])=[O:23].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17](/[CH:18]=[CH:25]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)=[N:10][CH:11]=1
Reactant: Cc1ccc(OCc2ccc(C=O)cc2)nc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(OCc2ccc(/C=C/[N+](=O)[O-])cc2)nc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 100.4 %

Procedure:
To an acetic acid (20.0 mL) solution of 4-(5-methyl-pyridin-2-yloxymethyl)-benzaldehyde (2.93 g, 12.9 mmol) described in Manufacturing Example 44-1-2 were added nitromethane (3.94 g, 64.5 mmol) and ammonium acetate (1.99 g, 25.8 mmol) under nitrogen atmosphere at room temperature, which was stirred for 2.5 hours at 100° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.50 g) as a crude product.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27](B1OC(C)(C)C(C)(C)O1)=[CH:26][CH:25]=2.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([CH3:21])=[CH:30]3)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (850 mg, 2.90 mmol) in DME (20 ml) was added 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.4 g, 5.44 mmol), potassium carbonate (751 mg, 5.43 mmol), Pd(PPh3)4 (157 mg, 0.14 mmol) and water (5 ml) under an inert atmosphere of nitrogen. The resulting solution was stirred for 1 h at 90° C. and then diluted with water (300 ml), extracted with ethyl acetate (3×100 ml), and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue, which was purified by a silica gel column (1%-5% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate as a yellow solid (660 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][C:5]([OH:12])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][C:5]2[O:12][C:9](=[O:10])[CH2:8][C:6]=2[CH:7]=1
Reactant: O=C(O)Cc1cc(Cl)c(C2CCCCC2)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1Cc2cc(Cl)c(C3CCCCC3)cc2O1

Procedure:
5 g of 5-chloro-4-cyclohexyl-2-hydroxyphenylacetic acid are dissolved in toluene with heating, 50 mg of p-toluenesulphonic acid are added, and the mixture is boiled in a water separator for 3 hours. The oil obtained after evaporation is purified on a 100-fold quantity of silica gel Merck. The desired product is eluted with chloroform and recrystallized from methylene chloride/petroleum ether. The crystals have an M.P. of 100°-102°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][C:10]2[C:11]3[NH:34][CH:33]=[CH:32][C:12]=3[N:13]=[C:14]([N:16]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:15]=2)=[C:4]([CH3:35])[CH:3]=1.[Li+].[CH3:37][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:35])[C:5]([S:9][C:10]2[C:11]3[N:34]([CH3:37])[CH:33]=[CH:32][C:12]=3[N:13]=[C:14]([N:16]([C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[N:15]=2)=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1Sc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2cc[nH]c12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(Br)cc(C)c1Sc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2ccn(C)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cold mixture of tert-butyl 4-(4-bromo-2,6-dimethylphenylthio)-5H-pyrrolo[3,2-d]pyrimidin-2-yl(4-cyanophenyl)carbamate (1.5 mmol) in THF (5 ml) at −78° C. is added a solution of LiHMDS (2 mmol). The mixture is warmed to 0° C. over 2 hours and then cooled to −78° C. Iodomethane (6 mmol) is added and the mixture warmed to room temperature over 2 hours and then stirred at room temperature for an additional 2 hours. The mixture is washed with brine and extracted with ethyl acetate (×3). The combined organic layers are dried over MgSO4 and concentrated to dryness. The crude material is purified by chromatography on silica.