Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])(=[O:3])[CH3:2].[O:11]=O.[OH-].[Na+:14]>O.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([O-:11])=[O:10])(=[O:3])[CH3:2].[Na+:14]
Reactant: CC(=O)NCCOCCO
Reactant: O=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NCCOCC(=O)[O-]
Temperature: 70 °C
Yield: 85 %

Procedure:
73.5 g of 5-acetylamino-3-oxa-1-pentanol were dissolved in 425 g of water, and 2.90 g of Pd/C (10% by weight) were added. The solution was heated to 70° C. and, while stirring vigorously, about 50 ml/min O2 were passed continuously through the solution under atmospheric pressure for 5 h. Throughout the reaction, the pH was kept at 10 by continuously metering in a total of 116 g of 20% by weight aqueous NaOH. The remaining solution was then extracted with ethyl acetate in a perforator for 3 days. The aqueous phase was then distilled to dryness to leave 77.8 g (corresponding to 85% of theory) of NMR-pure sodium 5-acetylamino-3-oxapentanoate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[N:29][CH:30]=1>>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([C:28]4[CH:27]=[CH:26][C:25]([C:24]([F:38])([F:39])[F:23])=[CH:30][N:29]=4)[CH2:32][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CN(c2ccc(C(F)(F)F)cn2)CCN1
Product: Cn1c2c(c3ccc(N4CCN(c5ccc(C(F)(F)F)cn5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 18.1 %

Procedure:
tert-Butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (300 mg, 0.821 mmol) and 4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-2-one (184 mg, 0.751 mmol) were reacted according to Example 2 (step f) to provide the title compound (72 mg, 18%): ESI MS m/z 530 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][C:6]([OH:8])=O)[CH:2]=[CH2:3].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[CH3:31][NH:32][O:33][CH3:34]>O1CCCC1>[CH2:1]([N:4]([CH2:5][C:6]([N:32]([O:33][CH3:34])[CH3:31])=[O:8])[C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CNOC
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
2-(Allyl(tert-butoxycarbonyl)amino)acetic acid (49.6 g, 156 mmol) is added to tetrahydrofuran (600 mL) at 0° C. followed by the addition of triethylamine (36.3 g, 359 mmol) and pivaloyl chloride (31 g, 353 mmol). The reaction is stirred at room temperature for 3 hours and then cooled to 0° C. N,O-dimethylhydroxylamine hydrochloride (28 g, 283 mmol), triethylamine (33 mL, 237 mmol) and tetrahydrofuran (400 mL) are then added. The ice bath is removed and the reaction stirred at room temperature for 3 hours and concentrated under reduced pressure. The resulting solid is dissolved in water and extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure to give a residue. The residue is purified by silica gel column chromatography, eluting with 0-50% gradient of acetone in hexanes to give the title compound (32 g, 54%). 1H NMR (CDCl3) mixture of two rotamers (60:40) δ 1.42, 1.44 (s, 9H), 3.16, 3.17 (s, 3H), 3.66, 3.69 (s, 3H), 3.88-3.98 (m, 2H), 4.01, 4.11 (s, 2H), 5.10-5.18 (m, 2H), 5.73-5.85 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[OH:10].[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[O:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(Br)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Br)cc1OC1CCCC1

Procedure:
20 g (0.1 mol) 1-Methoxy-2-hydroxy-4-bromo-benzene (Preparation 1) was dissolved in 40 ml ethanol. Then 21 g (0.14 mol) cyclopentylbromide and a solution of 5.5 g NaOH in 6.6 ml water was added and the mixture refluxed for 13 hours. Thereafter, the solvent was removed in vacuo and the residue taken up with methylene chloride and washed (4×) with 1N NaOH. After drying over Na2SO4, the organic solvent was removed in vacuo to give the title compound as an oily product, yield: 182 g (67%).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O>[N:21]1([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:7])=[CH:4][CH:3]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: O=C(Nc1cnc2ccccc2c1)c1ccc(F)cc1
Solvent: CS(C)=O
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(N2CCNCC2)cc1
Yield: 202.4 %

Procedure:
A solution of 4-fluoro-N-quinolin-3-yl-benzamide (2.0 g, 3.76 mmol) and piperazine (6.2 g, 72 mmol) in methylsulfoxide (30 mL) was heated 100° C. for 1.5 days, to give the product 2.53 g (100%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([CH2:30][S:31](Cl)(=[O:33])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][S:31]([CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:33])=[O:32])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NS(=O)(=O)Cc3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Sulfonylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with α-toluenesulfonyl chloride (12 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (25 ml) was performed according to the acylation method described in example 6.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[C:3]1[CH:12]=O.[CH3:14][NH2:15].[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[C:3]1[CH2:12][NH:15][CH3:14]
Reactant: Cc1cccc2cc(C=O)n(C)c12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc2cccc(C)c2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To 1,7-dimethyl-1H-indole-2-carbaldehyde (1.57 g, 9.06 mmol) was added a solution of 2 M solution of methylamine in methanol (30 mL) and the resulting mixture stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue taken up in ethanol (30 mL). The solution was cooled to 0° C. and then NaBH4 (0.34 g, 9.1 mmol) was added in one portion. The mixture was stirred overnight. Additional NaBH4 (0.18 g, 4.5 mmol) was added and the mixture was again stirred overnight. The mixture was concentrated under reduced pressure and the residue combined with 1 M NaOH (200 mL). The mixture was extracted with diethyl ether (3×150 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a pale yellow oil (1.60 g, 94%): 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=7.8 Hz, 1H), 6.93-6.87 (m, 2H), 6.34 (s, 1H), 4.02 (s, 3H), 3.84 (s, 2H), 2.77 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19]C(=O)C2C=CC=CC=2)=[N:10]1.N12CCCN=C1CCCCC2>CO>[NH2:19][C:11]1[O:12][C@H:13]([C:15]([F:17])([F:18])[F:16])[CH2:14][C@:9]([C:3]2[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=2[F:1])([CH2:28][F:29])[N:10]=1
Reactant: O=C(NC1=N[C@](CF)(c2cc(O)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@](CF)(c2cc(O)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
In a microwave vial was dissolved N-((4S,6S)-4-(2-fluoro-5-hydroxyphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (8d, 116 mg, 0.280 mmol) in MeOH (1120 μl) and added 1,8-diazabicyclo-[5.4.0]undec-7-ene (84 μl 0.560 mmol). The reaction mixture was stirred at 75° C. overnight. Cooled to room temperature. Concentrated down and used directly in the following step.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C@@H:23]([CH3:37])[C@@H:24]([CH3:36])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].[N+:44]([C:47]1[NH:48][CH:49]=[CH:50][N:51]=1)([O-:46])=[O:45]>>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([CH2:25][C@H:24]([CH3:36])[C@H:23]([CH3:37])[CH2:22][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:48]3[CH:49]=[CH:50][N:51]=[C:47]3[N+:44]([O-:46])=[O:45])[CH:15]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCOCCOCCOCCBr)c2)cc1OC
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCOCCOCCOCCn3ccnc3[N+](=O)[O-])c2)cc1OC
Yield: 85.1 %

Procedure:
The Standard Procedure 2 was followed by use of 5b (135.1 mg, 0.2315 mmol, 1.0 equiv), potassium carbonate (67.5 mg, 0.488 mmol, 2.1 equiv), and 2-nitroimidazole (6b, 54.3 mg, 0.485 mmol, 2.0 equiv). After workup and purification with column chromatography (80% EtOAc in hexanes as eluant), 7d (121.2 mg, 0.1970 mmol) was obtained in 85% yield as a yellow gummy oil: 1H NMR (CDCl3, 400 MHz) δ 0.81 (d, J=6.4 Hz, 6H, 2×CH3), 1.73 (m, 2H, 2×CH), 2.23-2.29 (m, 2H, 2×ArCH), 2.69-2.74 (m, 2H, 2×ArCH), 3.56-3.86 (m, 21H, 3×OCH3+6×OCH2), 4.12 (t, J=5.0 Hz, 2H, CH2N), 4.56 (t, J=4.8 Hz, 2H, CH2O), 6.62 (s, 1H, ArH), 6.67-6.69 (m, 3H, 3×ArH), 6.75-6.78 (m, 2H, 2×ArH), 7.08 (s, 1H, nitroimidazole C5-H), 7.23 (s, 1H, nitroimidazole C4-H); 13C NMR (CDCl3, 100 MHz) δ 16.05, 16.07, 38.63, 38.68, 39.09, 39.12, 49.71, 55.66, 55.76, 55.82, 68.30, 69.22, 69.58, 70.37, 70.46, 70.47, 70.61, 110.89, 111.56, 112.10, 114.58, 120.82, 121.56, 127.30, 127.86, 134.34, 134.40, 144.57, 146.88, 147.41, 147.77, 148.54; IR (neat) 2925 (s), 2873 (s), 1590 (w), 1538 (m), 1516 (s), 1456 (w), 1361 (s), 1260 (s), 1236 (s), 1029 (s) cm−1; HRMS (FAB) m/z calcd for C32H46N3O9 (M+H)+: 616.3234. found: 616.3231.
Reaction SMILES: [O:1]1[CH:3]2[C:4](=[O:30])[CH2:5][CH:6]3[C@:27]([CH3:28])([CH:2]12)[C@@H:26]1[C@H:9]([C@H:10]2[C@:23]([CH3:29])([CH2:24][CH2:25]1)[C@@H:13]([C:14]([CH3:22])=[CH:15][CH:16]=[CH:17][C:18]([F:21])([CH3:20])[CH3:19])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)(=O)C>[F:21][C:18]([CH2:17][CH2:16][CH2:15][C@H:14]([C@@H:13]1[C@:23]2([CH3:29])[C@H:10]([C@H:9]3[C@H:26]([CH2:25][CH2:24]2)[C@:27]2([CH3:28])[C:6](=[CH:5][C@@H:4]([OH:30])[CH2:3][C@@H:2]2[OH:1])[CH:7]=[CH:8]3)[CH2:11][CH2:12]1)[CH3:22])([CH3:19])[CH3:20]
Reactant: CC(=CC=CC(C)(C)F)[C@H]1CC[C@H]2[C@@H]3CCC4CC(=O)C5OC5[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](CCCC(C)(C)F)[C@H]1CC[C@H]2[C@@H]3C=CC4=C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
1,2-Epoxy-25-fluorocholestadien-3-one (0.01 mole) prepared according to 3A above is dissolved in 100 ml. of dry tetrahydrofuran under a nitrogen blanket at 0° C. and fresh lithium aluminum hydride (0.005 mole) is slowly added over 10 minutes with stirring. The mixture is stirred for 1.0 hour and 1.0 ml. of ethyl acetate is added to destroy the excess lithium aluminum hydride. Concentrated aqueous ammonium chloride (20 ml.) is added to the reaction mixture and the mixture is stirred for 5 minutes. Diethyl ether (200 ml.) is added to the reaction mixture, the mixture is well shaken and the organic layer separated. The organic layer is washed with water, dried with magnesium sulfate and the solvent is evaporated to give crude 25-fluoro-4,6-cholestadiene-1α,3β-diol. 25-Fluoro-4,6-cholestadiene-1α,3β-diol can be purified by chromatographing the crude product on a silica gel column using a solvent of petroleum ether and diethyl ether.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[N:17]=1>CN(C=O)C.C(OCC)C>[Cl:14][CH2:15][C:16]1[N:17]=[C:18]([CH3:22])[C:19]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:1](=[O:3])[CH3:2])=[CH:20][CH:21]=1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: ClCc1cccc(CCl)n1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccc(CCl)nc1C
Reaction time: 168 h
Yield: 59.9 %

Procedure:
To a solution of acetylsalicylic acid (1.6 g, 8.88 mmoles) in N,N′-dimethylformamide (20 ml) and under stirring sodium ethylate (0.64 g, 8.88 mmoles) is added. After 30 minutes the obtained solution is added to a solution of 2,6-bis-(chloromethyl)pyridine (4.72 g, 26.81 mmoles) in N,N′-dimethylformamide (20 ml). The solution is left at room temperature for 7 days, under stirring, then it is diluted with ethyl ether and washed with water. The separated organic phases are anhydrified with sodium sulphate and the solvent is evaporated at a reduced pressure. The reaction raw product is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 7/3. 1.7 g of the product as yellow oil are obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:5][C:6]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])[CH3:4].[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl>[C:28]([NH:1][CH2:2][C@@H:3]([NH:5][C:6]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])[CH3:4])(=[O:30])[CH3:29]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CN)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CNC(C)=O)cc1OC
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of (S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (99 mg) in dichloromethane (3 mL) was added acetic anhydride (38 mg), and the mixture was stirred for an hour at ambient temperature. The resulting mixture was evaporated in vacuo. The residue was triturated with diisopropyl ether to give (S)-2-[2-(acetamido)-1-methylethylamino]-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (107 mg) as a solid substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6](=O)[CH2:5]2.[BH4-].[Na+].Cl>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH:6]=[CH:5]2
Reactant: COc1ccc(CN2C(=O)Cc3cc(Br)ccc3C2=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-2-(4-methoxy-benzyl)-4H-isoquinoline-1,3-dione (product of step iii)) (2.6 g) in dichloromethane:methanol (3:1, 80 mL) was added sodium borohydride (1.0 g) portionwise over 2 hours. The reaction mixture was acidified with hydrochloric acid and stirred for 30 minutes. The reaction mixture was evaporated and the residue partitioned between dichloromethane and water. The organic phase was washed with brine, dried, filtered and evaporated. The residue was purified (SiO2, 1:4 ethyl acetate:iso-hexane as eluent) to yield the sub-title compound (1.2 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[N:9][N:10]=2)[N:7]=1.[SH-:11].[K+]>C(O)C>[SH:11][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[N:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2nnnn2n1
Reactant: [SH-]
Agent: [K+]
Solvent: CCO
Product: Sc1ccc2nnnn2n1

Procedure:
A mixture of 21.3 g. (0.137 mole) of 12 and 20 g. (0.25 mole) of potassium hydrosulfide in 200 ml. of ethanol was refluxed for 2 hours and evaporated to dryness. The residue was dissolved in 100 ml. of water and filtered to remove a small amount of insoluble material. The filtrate was acidified to pH 1 with dil. hydrochloric acid to precipitate (13) as colorless needles which were collected by filtration, washed with 20 ml. of water and dried. Yield 9.80 g. (47%). M.p. 140°-141° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.[CH2:18]=O>C(O)=O>[CH3:18][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: c1ccc2c(c1)CCC2CCC1CCCCN1
Reactant: C=O
Solvent: O=CO
Product: CN1CCCCC1CCC1CCc2ccccc21

Procedure:
45 g. of 1-[2-(2-piperidyl)-ethyl]indane prepared as described above is mixed with 100 ml. of 37% formalin and 200 ml. of 98% formic acid is added while swirling and the solution is then heated overnight on a steam bath. The reaction mixture is worked up by concentrating in vacuo, dissolving in water, filtering, basification and extraction with ether. The ether extracts are dried over potassium hydroxide and after removal of the ether, the product is distilled collecting 42.6 g. (88%), N-methyl-1-[2-(2-piperidyl)ethyl]indane, boiling point 128°-130° C/0.2 mm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9](Br)Br)=[CH:4][N:3]=1.C([OH:14])C>[N+]([O-])([O-])=O.[Ag+].O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:9]=[O:14])=[CH:6][C:7]=1[F:8]
Reactant: CCO
Reactant: Fc1cc(C(Br)Br)cnc1Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=Cc1cnc(Cl)c(F)c1

Procedure:
A suspension 2-chloro-5-(dibromomethyl)-3-fluoropyridine (2.3 g, 7.58 mmol), silver nitrate (5.15 g, 30.3 mmol) in a mixed solvents of ethanol (10 mL) and water (10 mL) was stirred for 1 h at 100° C., then filtrated, and concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate, concentrated. Purification via ISCO system afforded the title product (1.0 g) as a pale solid. LC-MS (ESI): m/z 159 [M+H]+; 2.01 min (ret time).
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].[H-].[Na+].I[CH2:40][CH3:41]>O1CCCC1>[C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:28][CH2:27][C@H:26]([N:29]([CH2:40][CH3:41])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)pyrrolidin-3-ylcarbamate (700 mg, 1.0 mmol) in tetrahydrofuran (11 mL) was added sodium hydride as a 60% dispersion in mineral oil (140 mg, 3.4 mmol) followed by iodoethane (0.77 mL, 9.4 mmol) and reaction mixture was stirred overnight at ambient temperature. The reaction was quenched with water (0.1 mL), diluted with ethyl acetate (100 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-60% ethyl acetate in heptane) to afford the title compound as a white solid, which was used in the next step without any further purification (560 mg. 80%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([OH:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([O:23][P:24](Cl)(=[O:28])[O:25][CH2:26][CH3:27])[CH3:22]>C(OCC)(=O)C>[P:24]([O:13][C:5]1[N:4]=[C:3]([N:2]([CH3:14])[CH3:1])[N:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:6]=1)([O:25][CH2:26][CH3:27])([O:23][CH2:21][CH3:22])=[O:28]
Reactant: CN(C)c1nc(O)cc(C(F)(F)F)n1
Reactant: CCOP(=O)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)Oc1cc(C(F)(F)F)nc(N(C)C)n1
Temperature: 40 °C

Procedure:
A mixture of 2-dimethylamino-4-trifluoromethyl-6-hydroxypyrimidine (3.1 G), anhydrous potassium carbonate (2.8 g), and dry ethyl acetate (50 ml) was refluxed together for 1 hour and then cooled to about 40° C. Diethylphosphorochloridate (2.54 g) was then added dropwise to the stirred mixture and when the addition was complete the mixture was refluxed for 16 hours, after which it was allowed to cool to the ambient temperature. After filtration to remove the solids present, the filtrate was washed with water (2 × 50 ml), 10% w/v aqueous sodium hydroxide solution (1 × 50 ml), and finally with water until the washings were neutral. The ethyl acetate solution was dried over anhydrous magnesium sulphate, and after filtering, the the solvent was evaporated under reduced pressure to yield a residual pale yellow oil, which on cooling and scratching yielded crystalline O,O-diethyl 2-dimethylamino-4-trifluoromethylpyrimidin-6-yl phosphate, melting point 22°-24° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:11]([O:13][C:14](Cl)=[O:15])[CH3:12]>N1C=CC=CC=1.ClCCl>[CH2:11]([O:13][C:14]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])=[O:15])[CH3:12]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To the solution of 2-nitroaniline (6.9 g, 50.0 mmol) in pyridine (6 mL) and dichloromethane (25 mL) at 0° C. under argon was added ethylchloroformate (7.3 mL, 75.0 mmol) through an addition funnel. After the addition was finished, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, saturated sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated to yield the title compound as a yellow solid (7.7 g, 73.3%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1Br.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>>[CH3:9][C:5]1[CH:4]=[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:2]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1ccc(N)cc1
Reactant: Cc1cc(Br)c(Br)cc1C
Product: Cc1ccc(Nc2cc(C)c(C)cc2Nc2ccc(C)cc2)cc1
Yield: 90.8 %

Procedure:
The synthesis is carried out in accordance with the general procedure in accordance with Example 2 from 63.3 g (240 mmol) of 1,2-dibromo-4,5-dimethylbenzene and 54 ml (505 mmol) of p-toluidine. The precipitated solid is recrystallised from toluene/acetonitrile (5:1), and the residue is washed with MeOH, giving 69 g (218 mmol) of a crystalline solid. The overall yield is 91%.