Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][N:27](C(OCC3C=CC=CC=3)=O)[CH2:28][CH:29]=2)=[CH:20][CH:19]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].C(OCC)C.C(OCC)(=O)C>CO.[Pd]>[NH:27]1[CH2:28][CH2:29][CH:24]([C:21]2[CH:22]=[CH:23][C:18]([C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:17])=[CH:19][CH:20]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2=CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Temperature: 50 °C
Yield: 80.6 %

Procedure:
To a solution of benzyl 4-{4-[({2-[(tert-butoxycarbonyl)amino]phenyl}amino)carbonyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (269 g, 524 mmol; prepared as described in Method 2 below) in methanol (3000 ml) was added 10% palladium on charcoal (10 g). The reaction mixture was placed under 5 bar pressure of hydrogen gas and heated to 50° C. for 1 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite and the solvent evaporated under reduced pressure. The resultant foam was triturated under diethyl ether and filtered to give a white solid. This product was ground finely and stirred with 95:5 diethyl ether/ethyl acetate then collected by suction filtration. This solid was washed with diethyl ether, isohexane and dried in vacuo to afford the title compound (167 g, 81%); NMR Spectrum: (DMSO-d6) 1.45 (s, 9H), 1.57 (m, 2H), 1.72 (m, 2H), 2.61 (t, 2H), 2.69 (m, 1H), 3.07 (m, 2H), 7.18 (m, 2H), 7.40 (d, 2H), 7.53 (d, 2H), 7.91 (d, 2H), 8.70 (br s, 1H), 9.82 (br s, 1H); Mass Spectrum: M+H+396.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:3]1([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](N[C@H]1CCNC1)c1cccc2ccccc12
Reactant: Brc1ncccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](N[C@H]1CCN(c2ncccn2)C1)c1cccc2ccccc12
Yield: 70.4 %

Procedure:
To a suspension of 156.6 mg of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride in 5 ml of dioxane were added 87.4 mg of 2-bromopyrimidine and 207 mg of diisopropylethylamine, and the mixture was stirred under reflux for 16 hours. The reaction mixture was evaporated, and to the residue were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:240:1) to obtain 112 mg of (R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine. (2) In 10 ml of ethyl acetate was dissolved 112 mg of (R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine, and 1 ml of a solution of 4M hydrochloric acid in ethyl acetate was added to the mixture and the resulting mixture was stirred. The reaction mixture was concentrated under reduced pressure, to the residue was added diethyl ether, precipitates were collected by filtration and washed with ethyl acetate, to obtain 68.3 mg of (R)-1-(naphthalen-1-yl)ethyl-[(S)-1-(pyrimidin-2-yl)pyrrolidin-3-yl]amine dihydrochloride (the following Table A2, Example 2.010).
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)(=O)C>CO>[N:15]1([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
Under a nitrogen atmosphere, add sodium cyanoborohydride (5.77 g, 91.6 mmol) to a solution of 4-cyanobenzaldehyde (3 g, 22.9 mmol), piperidine (5.84 g, 68.7 mmol) and acetic acid (2.75 g, 45.8 mmol) in methanol (30 mL) at 0° C. with stirring. Warm the mixture to room temperature and stir overnight. Add water (100 mL), saturated aqueous K2CO3 (50 mL), and extract with DCM. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel (400 g) eluting with hexane/EtOAc (1:0 to 4:1 gradient) to obtain the desired intermediate as a clear oil (2.48 g, 54%). MS (APCI+) m/z: 201 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4](Br)[N:3]=1.O.[NH2:18][NH2:19]>CCO>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4]([NH:18][NH2:19])[N:3]=1
Reactant: Cc1nc(N2CCN(C)CC2)c(Br)nc1Br
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1nc(N2CCN(C)CC2)c(NN)nc1Br
Yield: 53.6 %

Procedure:
A 100 mL round bottom flask was charged with 2,6-dibromo-3-methyl-5-(4-methylpiperazin-1-yl)pyrazine (2.0 g, 5.7 mmol), hydrazine hydrate (3.5 g, 0.065 mol) and absolute EtOH (30 mL). The resulting solution was refluxed under N2 atmosphere overnight. Work-up: the solvent was evaporated. The residue was washed with EtOH (10 mL) and dried, to afford 0.92 g (54%) of the product as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.Cl.[CH2:11]([O:13][C:14](=[O:17])[CH2:15][NH2:16])[CH3:12].ClC(Cl)C.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:16][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:17])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCc1cccc(Br)n1
Reaction time: 0.75 h

Procedure:
6-Bromopyridine-2-carbaldehyde (10 g, 53.8 mmol) and glycine ethyl ester hydrochloride (7.50 g, 53.8 mmol) were placed in a flask. Dichloroethane (220 mL) and triethylamine (7.49 mL, 53.8 mmol) were added and the reaction was stirred for 45 minutes. Sodium triacetoxyborohydride (15.95 g, 75 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction was diluted with ethyl acetate, saturated sodium bicarbonate, and saturated sodium carbonate to make the pH basic. The organic layer was separated and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]2[C:23](=[O:53])[CH:24]([CH2:27][C:28]3[N:29]=[CH:30][N:31]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:32]=3[CH3:33])[CH2:25][CH2:26][C:15]=12.CI.C(O)(=O)C(O)=O>O1CCCC1.CCCCCC.O>[CH3:1][C:24]1([CH2:27][C:28]2[N:29]=[CH:30][N:31]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:32]=2[CH3:33])[C:23](=[O:53])[N:16]2[C:17]3[C:22]([C:14]([CH3:13])=[C:15]2[CH2:26][CH2:25]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: CC(C)NC(C)C
Reactant: Cc1c2n(c3ccccc13)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Agent: O=C(O)C(=O)O
Agent: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c2n(c3ccccc13)C(=O)C(C)(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reaction time: 0.33 h
Yield: 66.5 %

Procedure:
To a solution of diisopropylamine (263 mg) in tetrahydrofuran (3 ml) at -70° C. under a nitrogen atmosphere was added 1.64M butyllithium in hexane (1.75 ml). After being stirred at the same temperature for 20 minutes, the mixture was treated with a solution of 8,9-dihydro-10-methyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (1.07 g) in tetrahydrofuran (5 ml) over 15 minutes. The mixture was stirred at -65° C. for 30 minutes and at -25° C. for 40 minutes and a solution of methyl iodide (282 mg) in tetrahydrofuran (3 ml) was added dropwise at -65° C. over 10 minutes. After the mixture was stirred at -65° C. for 30 minutes and at -20° C. for 1 hour, it was diluted with water and neutralized with an aqueous solution of oxalic acid. The resultant mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification of the residue with silica gel column chromatography (5% ethyl acetate-chloroform) gave 8,9-dihydro-7,10-dimethyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (0.73 g).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cccnc2)C1
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amine 17 (100 mg, 0.34 mmol) and piperidinomethyl polystyrene resin (100 mg) in 1 mL of dry CH2Cl2 was added propionyl chloride (30 μL, 1 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded N-(1-Boc-piperidin-3-ylmethyl)propionamide 18 (85 mg, 71%). LRMS 248 (M-100)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[CH:10][C:4]=2[C:3]=1/[C:27](=[N:29]/[OH:30])/[NH2:28].[OH:31][C:32]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33]1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=3)(=[O:19])=[O:18])[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[CH:10][C:4]=2[C:3]=1/[C:27](=[N:29]/[O:30][C:36]([C:32]1([OH:31])[CH2:35][CH2:34][CH2:33]1)=[O:37])/[NH2:28]
Reactant: O=C(O)C1(O)CCC1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(/C(N)=N/O)c(Cl)cnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(/C(N)=N/OC(=O)C4(O)CCC4)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (Z)-5-chloro-N′-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carboximidamide (Example 138B) (44 mg, 0.099 mmol), 1-hydroxycyclobutanecarboxylic acid (12.63 mg, 0.109 mmol), 1-hydroxybenzotriazole hydrate (7.57 mg, 0.049 mmol), and 4-methylmorpholine (0.038 mL, 0.346 mmol) in anhydrous dimethylformamide (1 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (28.4 mg, 0.148 mmol). The reaction was stirred for 3 hours at ambient temperature. The reaction was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound. MS ESI(+) m/z 542.9 [M+H]+.
Reaction SMILES: F[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:24]1[NH:28][C:27]([CH3:29])=[N:26][CH:25]=1.CC1NC(C2C=C(C=CC=2F)C([N:42]2[CH2:47][CH2:46][CH:45](C3C=CC(C#N)=CC=3)CC2)=O)=C(C)N=1>>[N:42]1([C:2]2[CH:23]=[CH:22][C:5]([C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)[CH2:10][CH2:9]3)=[O:7])=[CH:4][C:3]=2[C:24]2[NH:28][C:27]([CH3:29])=[N:26][CH:25]=2)[CH2:45][CH2:46][CH2:47]1
Reactant: Cc1ncc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2F)[nH]1
Reactant: Cc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2F)[nH]1
Product: Cc1ncc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2N2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 25, except 4-(1-(4-fluoro-3-(2-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 132.3) was used in place of 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)piperidin-4-yl)benzonitrile (compound 25.1). m/z (ES+) 426 (M+H)+.
Reaction SMILES: [NH:1]([CH2:5][C@@H:6]1[O:18][C@H:17]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)[C:2]([NH2:4])=[O:3].N1C=CC=CC=1.[CH3:34][C:35](=[CH:39][O:40][CH3:41])[C:36](Cl)=[O:37].P(O)(O)([O-])=O.[K+]>C(Cl)Cl>[CH3:34][C:35](=[CH:39][O:40][CH3:41])[C:36]([N:1]([CH2:5][C@@H:6]1[O:18][C@H:17]([CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)[C:2]([NH2:4])=[O:3])=[O:37]
Reactant: COC=C(C)C(=O)Cl
Reactant: NC(=O)NC[C@H]1C[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC=C(C)C(=O)N(C[C@H]1C[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
In 32.2 ml of methylene chloride was dissolved 2.3 g of 1-ureido-2,5-anhydro-4,6-di-O-benzyl-1,3-dideoxy-D-allitol followed by addit ion of 9.2 ml of pyridine. Then, 1.67 g of 2-methyl-3-methoxypropenoyl chloride was added and the mixture was stirred at room temperature overnight. This reaction mixture was poured in 5% aqueous solution of monopotassium phosphate followed by extraction with ethyl acetate. The organic layer was washed with 5% aqueous monopotassium phosphate solut ion thrice, saturated aqueous sodium hydrogen carbonate solution once, and saturated aqueous sodium chloride solution once in turn, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (chloroform→1% methanol/chloroform) to provide 2.3 g of the desirable compound as pale-yellow oily substance.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:21][NH:22][C@H:23]([C@H:29]([OH:35])[C:30](OCC)=[O:31])[C:24](OCC)=[O:25])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>C(OCC)C.CO>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:21][NH:22][C@H:23]([CH2:24][OH:25])[C@H:29]([OH:35])[CH2:30][OH:31])=[CH:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](O)[C@@H](NCc1cn(COCc2ccccc2)c2c(OC)ncnc12)C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: COc1ncnc2c(CN[C@H](CO)[C@H](O)CO)cn(COCc3ccccc3)c12
Yield: 66.2 %

Procedure:
To a stirred solution of the product from Example 17.1 (1.718 g, 3.53 mmol) in diethyl ether (30 ml) was added methanol (1.43 ml, 35.3 mmol) and then lithium borohydride (8.83 ml, 17.7 mmol, 2.0M in THF). After 1 h methanol (1.43 ml, 35.3 mmol) was added to the reaction mixture and stirring continued. After 1 h further the reaction mixture was diluted with methanol and then concentrated. The residue was dissolved in methanol (20 ml), diluted with hydrochloric acid (20 ml, 1M) and concentrated. The residue was chromatographed on silica gel (methanol [7N ammonia]-DCM, 15:85) giving a white solid (0.940 g, 66%). 1H NMR (CD3OD) δ 8.43 (s, 1H), 7.69 (s, 1H), 7.28-7.15 (m, 5H), 5.77 (s, 2H), 4.52 (s, 2H), 4.12 (ABq, 2H), 4.11 (s, 31-1), 3.80 (dd, J=11.7, 5.3 Hz, 1H), 3.80-3.60 (m, 3H), 3.59 (dd, J=11.0, 4.9 Hz, 1H), 2.90 (q, J=4.9 Hz, 1H). 13C NMR (CD3OD) δ 158.4, 151.4, 151.0, 139.1, 135.0, 129.7, 129.2, 129.1, 117.5, 115.3, 79.0, 72.5, 72.0, 65.6, 62.0, 61.6, 54.8, 42.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:17]([O-])=O)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2>O1CCCC1.C(OCC)(=O)C.ClCCl.[Pd]>[NH2:17][C:3]1[C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[N:8]2
Reactant: COc1nc2cc(Cl)c(Cl)c([N+](=O)[O-])c2nc1OC
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc2cc(Cl)c(Cl)c(N)c2nc1OC
Reaction time: 22 h
Yield: 78.5 %

Procedure:
6,7-Dichloro-2,3-dimethoxy-5-nitroquinoxaline (20 g, 0.066 mol) and 5% w/w palladium-on-carbon (50% wet) (1.2 g) were suspended in a mixture of tetrahydrofuran (0.12 L) and ethyl acetate (0.12 L). The mixture was hydrogenated at 60° C. and 414 kPa (60 psi) for 22 hours, cooled, diluted with dichloromethane (0.48 L) and the catalyst removed by filtration through celite (trade mark) filter aid. The solution was concentrated under reduced pressure with the gradual addition of toluene. The mixture was then filtered and the solid was washed with toluene (20 ml) to give the title compound as a brown solid (14.2 g, 78%), m.p. 182-4° C.
Reaction SMILES: [F:1][C:2]1([F:31])[CH2:3][CH2:4][N:5]([C:17]([C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:30])=[O:18])[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2/[C:8]/1=[CH:9]/[C:10]([OH:12])=O.ON1C2C=CC=CC=2N=N1.[ClH:42].C(N=C=NCCCN(C)C)C.[CH2:54]([N:61](CC1C=CC=CC=1)[CH2:62][CH2:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)C>[ClH:42].[F:1][C:2]1([F:31])[CH2:3][CH2:4][N:5]([C:17]([C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:30])=[O:18])[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:67]1[CH2:66][CH2:65][CH:64]([CH2:63][CH2:62][NH:61][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:69][CH2:68]1)=[O:12]
Reactant: c1ccc(CN(CCC2CCNCC2)Cc2ccccc2)cc1
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(CCNCc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.5 %

Procedure:
To a solution of 260 mg of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetic acid in 20 ml of tetrahydrofuran were added 118 mg of 1-hydroxybenzotriazole, 167 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydro-chloride, 600 mg of (dibenzyl) [2-(4-piperidyl)ethyl]amine and 310 μl of triethylamine, and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over magnesium sulfate, and the solvent was evaporated therefrom. The resulting residue (385 mg) was dissolved in 10 ml of dichloroethane, 64 μl of 1-chloroethyl chloroformate was added thereto, and the mixture was stirred with heating under refluxing for 4.5 hours. The solvent was evaporated, 10 ml of methanol was added to the residue, and the mixture was stirred with heating under refluxing for 4.5 hours. After cooling to room temperature, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate, and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (eluting with chloroform-methanol). The resulting residue (22 mg) was dissolved in 0.1 ml of ethyl acetate, then 30 μl of a 4N HCl/ethyl acetate solution was added to the solution, and the mixture was stirred at room temperature. The solvent was evaporated therefrom, and the resulting solid was collected by filtration to give 14 mg of (Z)-4,4-difluoro-5-(2-{4-[2-(benzylamino)ethyl]piperidino)-2-oxoethylidene)-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepine monohydrochloride as a colorless powder.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[F-].[Cs+]>CN(C=O)C.O.CCOC(C)=O>[CH2:1]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(N2CCc3c([nH]c4ccccc34)C2)cc1
Temperature: 65 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (250 mg, 1.460 mmol) in dry DMF (10 mL) were added 4-fluorobenzaldehyde (181 mg, 1.460 mmol) and CsF (266 mg, 1.752 mmol) and the reaction mixture was stirred at 65° C. for 5 hours. After completion, the reaction mixture was diluted with water (25 mL) and EtOAc (25 mL). The organic layer was separated and the aqueous layer was washed twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulphate and concentrated under vacuum to provide the crude compound. It was then purified by column chromatography using silica gel to obtain 4-(1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)benzaldehyde (125 mg). 1H NMR (CDCl3+DMSO-D6, 200 MHz) ppm: 9.93 (1H, bs), 9.74 (1H, s), 7.99 (1H, s), 7.76 (2H, d, J=8.8 Hz), 7.44 (1H, m), 7.32 (1H, m), 7.13-6.97 (3H, m), 4.61 (2H, s), 3.86 (2H, t, J=5.6 Hz), 2.93 (2H, m); m/e=277 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH:23]([CH3:26])[CH2:24][NH2:25])[N:19]2[CH:27]=[CH:28][N:29]=[C:18]2[CH:17]=1.Cl[C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>O>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH:23]([CH3:26])[CH2:24][NH:25][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=2)[N:19]2[CH:27]=[CH:28][N:29]=[C:18]2[CH:17]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(CN)Nc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CNc1ccc(C#N)cn1)Nc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Temperature: 150 °C

Procedure:
The amine (Example 37A) (300 mg, 0.46 mmol), 2-chloro-5-cyanopyridine (129 mg, 0.93 mmol) and N,N-diisopropylethylamine (600 mg, 4.6 mmol) are introduced into DMSO (6 ml), and heated at 150° C. in a microwave oven for 30 min. The reaction mixture is poured into water and extracted with ethyl acetate (3×25 ml). The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The residue is taken up in acetonitrile, and the product precipitates and is washed with acetonitrile and dried. 87 mg (41% of theory) of the product are obtained as a solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1>>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([Cl:3])=[O:16])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccc(Cl)cc1
Product: O=C(Cl)CCc1ccc(Cl)cc1
Reaction time: 20 h
Yield: 100 %

Procedure:
Thionyl chloride (16.31 g, 137.09 mmol) was added to 3-(4-chlorophenyl)propionic acid (3.0 g, 16.25 mmol) at room temperature. The reaction mixture was stirred for 20 hours, then concentrated to afford 3.3 g of 3-(4-chlorophenyl)propionyl chloride.