Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]2[N:14]=[CH:15][CH:16]=[C:4]2[N:3]=1.C([O-])(=O)C.[Na+]>[Pd]>[C:8]1([C:6]2[CH:7]=[CH:2][N:3]3[N:14]=[CH:15][CH:16]=[C:4]3[N:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cc(-c2ccccc2)n2nccc2n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: c1ccc(-c2ccn3nccc3n2)cc1
Reaction time: 0.75 h

Procedure:
A mixture of 2.29 g. of 5-chloro-7-phenylpyrazolo-[1,5-a]pyrimidine, 0.90 g. anhydrous sodium acetate, and 0.30 g. of 10% palladium on charcoal catalyst in 100 ml. of absolute alcohol is hydrogenated at 10 lbs. pressure. Uptake stops in 45 minutes and catalyst is filtered. Evaporation and solution in methylene chloride with passage through a short hydrous magnesium silicate column gives the solution from which the desired compound crystallizes upon the addition of hexane, m.p. 122°-124° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([C:5]#[N:6])[C:3]#[N:4].[C:8](#[N:10])[CH3:9].O>C1(C)C=CC=CC=1>[NH2:4][C:3]([C:2]([CH3:7])([CH3:1])[C:5]#[N:6])=[CH:9][C:8]#[N:10]
Reactant: CC#N
Reactant: CC(C)(C#N)C#N
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C#N)C(N)=CC#N
Temperature: 40 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of potassium tert amylate in toluene (25%, 11.8 mL, 23 mmol) is added slowly to a solution of 2,2-Dimethyl-malononitrile (2.0 g, 21 mmol) and acetonitrile (1.2 mL, 23 mmol) in toluene (20 mL) at 40° C. under argon. The reaction mixture is stirred at 40° C. for 2 h and then cooled to 12° C. Water (5 mL) is added and the mixture is stirred at 20° C. for 15 min and at 2° C. for 30 min. Filtration, washing with cold water (10 mL) and drying under vacuum provides 2.30 g 3-Amino-4,4-dimethyl-pent-2-endinitrile. Yield: 80%: ESI-MS: 136 [M+H]+; 1H-NMR (DMSO-d6): 1.5, 4.1, 6.8 ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[O:28])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared as in Example 1(B)(f), 600 mg, 1.36 mmol) in absolute ethanol (6 mL) was treated with a 1N aqueous sodium hydroxide solution (2.85 mL, 2.85 mmol). The reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove absolute ethanol. The resulting yellow residue was acidified to pH=2 with concentrated hydrochloric acid and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Precipitation from 1/1 hexanes/ethyl acetate afforded 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-4-carboxylic acid (399 mg, 71%) as a white solid: mp 285-287° C.; FAB-HRMS m/e calcd for C18H18Cl2N2O3S (M+H)+ 413.0493, found 413.0481.
Reaction SMILES: C([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[CH:8]=1)(C)(C)C.[C:16](O)(=O)[C:17]1[CH:22]=CN=C[CH:18]=1>>[ClH:13].[CH2:6]([C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([CH2:22][CH:17]([CH3:16])[CH3:18])[N:10]=1)[C:6]([OH:5])=[O:15])[CH:7]([CH3:12])[CH3:8]
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1
Product: CC(C)Cc1cc(C(=O)O)cc(CC(C)C)n1
Product: Cl

Procedure:
2,6-Diisobutyl-isonicotinic acid hydrochloride is prepared starting from 2,6-dichloro-isonicotinic acid tert.-butyl ester and 2,4,6-tri-(2-methyl-propenyl)-cycloboroxane pyridine complex in analogy to isonicotinic acid 7; LC-MS: tR=0.68 min; [M+1]+=236.40; 1H NMR (D6-DMSO): δ 7.90 (s, 2H), 2.92 (d, J=6.3 Hz, 4H), 2.10 (hept, J=6.8 Hz, 2H), 0.90 (t, J=6.5 Hz, 6H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=1[F:37])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:38][C@H:39](O)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.ClCCl>[CH2:20]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([O:34][C@H:39]([CH3:38])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:33])=[CH:30][C:29]=1[F:37])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: CCCCCC[C@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)OC(=O)c1ccc(OCc2ccccc2)c(F)c1

Procedure:
Triphenylphosphine (7.92 g, 30 mmol) in THF (40 ml) was added dropwise to a stirred solution of compound 11 (7.00 g, 28 mmol), (S)-(+)-octan-2-ol (3.66 g 28 mmol) and diethyl azodicarboxylate (4.87 g, 28 mmol) in THF (100 ml). The reaction solution was left stirring under nitrogen until completion [reaction monitored by TLC (dichloromethane, silica)]. Upon completion, the solvent was removed in vacuo to yield a colourless solid which was purified by column chromatography (dichloromethane) on silica to yield a colourless oil. Yield 10.01 g (99%), [α]D=−22.4° at 25° C.
Reaction SMILES: FC1(F)CC1CN1CCN(C2SC(C(OCC)=O)=C(C)N=2)C1=O.[CH:24]1([CH2:27][N:28]2[C:32](=[O:33])[N:31]([C:34]3[S:35][C:36]([C:40]([O:42]CC)=[O:41])=[C:37]([CH3:39])[N:38]=3)[CH:30]=[N:29]2)[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][N:28]2[C:32](=[O:33])[N:31]([C:34]3[S:35][C:36]([C:40]([OH:42])=[O:41])=[C:37]([CH3:39])[N:38]=3)[CH:30]=[N:29]2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1sc(-n2cnn(CC3CC3)c2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Product: Cc1nc(-n2cnn(CC3CC3)c2=O)sc1C(=O)O
Yield: 92 %

Procedure:
Following the procedure as described in Preparation 14, making variations as required to replace ethyl 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with ethyl 2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 92% yield: 1H NMR (300 MHz, DMSO-d6) δ13.39 (br s, 1H), 8.72 (s, 1H), 3.63 (d, J=7.1 Hz, 2H), 2.57 (s, 3H), 1.19-1.04 (m, 1H), 0.53-0.42 (m, 2H), 0.36-0.27 (m, 2H); MS (ES−) m/z 279.0 (M−1).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3](=O)[CH2:4][C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C1C=CC=CC=1.[CH3:21][C:22]([N:25]1[C:29]([NH2:30])=[CH:28][C:27]([CH3:31])=[N:26]1)([CH3:24])[CH3:23]>C(O)(=O)C>[CH3:24][C:22]([N:25]1[C:29]2[N:30]=[C:3]([C:2]([CH3:14])([CH3:13])[CH3:1])[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:28]=2[C:27]([CH3:31])=[N:26]1)([CH3:21])[CH3:23]
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Reactant: CCOC(=O)C(=O)CC(=O)C(C)(C)C
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C(C)(C)C)nc2c1c(C)nn2C(C)(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 5,5-dimethyl-2,4-dioxohexanoate (392 mg, 1.958 mmol), benzene (10 mL), 1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (300 mg, 1.958 mmol), and acetic acid (2 mL). The crude product was purified by column chromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give 530 mg (85%) of product. LCMS E-S (M+H)=318.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-1.52 (m, 12H), 1.84 (s, 9H), 2.67 (s, 3H), 4.50 (q, J=7.07 Hz, 2H), 7.59 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([CH2:19][CH3:20])[NH:5][N:4]=1)[CH3:2].Cl.Cl[CH2:23][CH2:24][NH2:25]>>[NH3:4].[NH2:25][CH2:24][CH2:23][N:5]1[C:6]([CH2:19][CH3:20])=[C:7]([CH2:8][C:9]2[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=[C:11]([CH:10]=2)[C:17]#[N:18])[C:3]([CH2:1][CH3:2])=[N:4]1
Reactant: CCc1n[nH]c(CC)c1Cc1cc(C#N)cc(C#N)c1
Reactant: NCCCl
Agent: Cl
Product: CCc1nn(CCN)c(CC)c1Cc1cc(C#N)cc(C#N)c1
Product: N
Temperature: 150 °C
Yield: 83 %

Procedure:
A stirred mixture of the pyrazole (106 mg, 0.4 mmol) of Example 91 and 2-chloroethylamine hydrochloride (70 mg, 0.6 mmol) was heated at 150° C. under nitrogen for 18 hours. After cooling the mixture was partitioned between 10% aqueous potassium carbonate (40 ml) and dichloromethane (40 ml) and the organic layer was dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (98:2, by volume) and then dichloromethane:methanol:0.880 ammonia (95:5:0.5, by volume) to give the title compound as a white solid (51 mg) m.p. 100-105°C.
Reaction SMILES: [BrH:1].S(=O)(=O)(O)O.[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23]O)=[CH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>O>[Br:1][CH2:23][CH2:22][O:21][CH2:20][CH2:19][NH:18][C:12]1[C:11]2[C:16](=[CH:17][C:8]([Cl:7])=[CH:9][CH:10]=2)[N:15]=[CH:14][CH:13]=1
Reactant: OCCOCCNc1ccnc2cc(Cl)ccc12
Reactant: Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Clc1ccc2c(NCCOCCBr)ccnc2c1
Temperature: 155 °C
Yield: 31 %

Procedure:
Hydrobromic acid (5.9 ml, 109.1 mmol) and then sulphuric acid (2.0 ml, 37.0 mmol) are added dropwise to 4.7 g of compound 21 (17.6 mmol), the reaction medium being refrigerated using a bath of cold water. The reaction medium is then heated at 155° C. for 2 h 30 min, and then poured into 70 ml of cold water. The pH is then adjusted by adding NaHCO3 (pH approximately 9), and the medium is then extracted at the reflux of toluene (70 ml) for 20 min. The organic phase is then collected and the compound 22 is obtained after crystallization at −18° C. overnight, filtration, washing with hexane, and then drying under vacuum: 1.77 g (yield=31%).
Reaction SMILES: [CH3:1][C@@:2]12[C:18]([C:19]#[N:20])=[CH:17][CH2:16][C@@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:21])[CH2:11][CH2:10][C@H:9]([O:22]COC)[CH2:8]3)[CH2:3]2.Cl>CO.ClCCl>[CH3:1][C@@:2]12[C:18]([C:19]#[N:20])=[CH:17][CH2:16][C@@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:21])[CH2:11][CH2:10][C@H:9]([OH:22])[CH2:8]3)[CH2:3]2
Reactant: COCO[C@H]1CC[C@]2(C)[C@H](CC[C@@H]3C[C@]4(C)C(C#N)=CC[C@@H]4C[C@H]32)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@@]12CC[C@H](O)C[C@H]1CC[C@@H]1C[C@]3(C)C(C#N)=CC[C@@H]3C[C@H]12
Reaction time: 14 h
Yield: 93.7 %

Procedure:
To compound 26 (125 mg, 0.36 mmol) in methanol (9 mL) and dichloromethane (3 mL) was added 6 N HCl (10 ml) at room temperature. After 14 h, the mixture was extracted with dichloromethane (50 mL×2). The combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexanes) to afford compound 27 (101 mg, 93%): mp 170-172° C., [α]D25+5.4 (c 0.24, CHCl3); 1H NMR (CDCl3) δ 6.61 (t, J=2.8 Hz, 1H), 4.04-4.02 (m, 1H), 0.89 (s, 3H), 0.78 (s, 3H); 13C NMR (CDCl3) δ 147.7, 127.3, 116.0, 66.3, 55.1, 50.5, 48.1, 42.2, 39.1, 36.4, 35.7, 35.0, 34.8, 32.3, 32.0, 28.8, 28.7, 22.4, 16.6, 11.1; IR νmax 3391, 2216, 1448 cm−1. Anal. Calcd for (C20H29NO): C, 80.22; H, 9.76; N, 4.68. Found: C, 80.32; H, 9.70; N, 4.72.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:42][CH:43]=[CH:44][C:30]=34)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:42][CH:43]=[CH:44][C:30]=34)[CH2:27][CH2:28]2)=[O:22])=[CH:6][CH:7]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
(S)-tert-Butyl 2-(4-chlorophenyl)-3-(4-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.040 g, 0.064 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (S)-2-(4-chlorophenyl)-1-(4-(5-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (0.020 g, 60% yield) as the dihydrochloride salt. MS ESI (+) m/z 521 detected.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:29])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([C:25](=[O:27])[CH3:26])[C@@H:9]([CH3:28])[CH2:8]1)[CH3:3].C(O)(=O)C.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[NH3:6].[C:25]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:29])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:28])(=[O:27])[CH3:26]
Reactant: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Product: N
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A suspension of 1-methylethyl[(2S,4R)-1-acetyl-6-(4-formylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 68) (1.078 g, 2.73 mmol) in dichloromethane (DCM) (20 mL) under nitrogen was treated with acetic acid (0.313 mL, 5.47 mmol) and piperidine (0.279 g, 3.28 mmol). The resulting mixture was stirred at room temperature for 1 h then sodium triacetoxyborohydride (0.695 g, 3.28 mmol) was added and the reaction left to stir at room temperature over 60 h then concentrated in vacuovacuo. The residue was partitioned between a saturated NaHCO3 aqueous solution (25 mL) and AcOEt (40 mL) and the layers were separated. The aqueous phase was extracted with AcOEt (25 mL) and the combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuovacuo. The residue was loaded on a 20 g SCX cartridge and eluted with MeOH (45 mL) then with 2M NH3 in MeOH (2×45 mL). The ammonia fractions were combined and concentrated in vacuo to give a first residue. The methanol fractions were concentrated and the residue obtained was loaded on a 20 g SCX cartridge and eluted with MeOH (45 mL) then with 2M NH3 in MeOH (2×45 mL). The ammonia fractions were combined and concentrated in vacuo to give a second residue. The two residues were combined and purified by flash chromatography on silica gel using an SP4 and a 100 G cartridge (gradient:1 to 5% (2M NH3 in MeOH) in DCM) to give 1-methylethyl {(2S,4R)-1-acetyl-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (0.9195 g, 1.884 mmol, 68.9% yield) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:35])[NH2:14])=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of 7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (0.66 g) in tetrahydrofuran (150 mL) was added Lawesson's reagent (0.89 g), and the mixture was stirred at 50° C. for 1 h. Tetrahydrofuran (100 mL) and Lawesson's reagent (0.42 g) were added to the mixture. After stirring at 50° C. for 13 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80 to 100/0, volume ratio) to give the title compound (0.68 g, 99%) as a yellow amorphous solid. MS 378 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH2:14].C1COCC1>C(O)C>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH:9]([OH:10])[CH2:11][NH:14][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC1CO1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCO
Product: CNCC(O)CNC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A solution of Oxiranylmethyl-carbamic acid tert-butyl ester (0.64 g, 3.7 mmol) in Ethanol (6 mL) was treated at room temperature with a 2.0M solution of methylamine in THF (5 mL, 10 mmol). The reaction mixture was stirred for 5 hours at 40° C. The solvent was evaporated in vacuo to yield a gum which was used directly into the next step (0.75 g, 98%)
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22]I)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[NH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CO>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22][NH:24][CH2:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Reactant: NCCc1cccnc1
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNCCc3cccnc3)ccc21
Temperature: 50 °C
Reaction time: 9 h
Yield: 69.8 %

Procedure:
1-Ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (5.3 mmol) was added to a methanol solution (100 ml) of 3-(2-aminoethyl)pyridine (3.3 g, 26.7 mmol), and stirred at 50° C. for 9 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water was added to the residue, and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate:methanol=1:0→10:1) again. The purified product was concentrated under reduced pressure to thereby obtain 1.57 g (yield: 70%) of 1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([O:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)=[O:13])([CH3:9])[C:5]([F:8])([F:7])[F:6].[CH3:22][Al](C)C.CCCCCCC.[Li]C.CCOCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]([O:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)([OH:13])[CH3:22])([CH3:9])[C:5]([F:8])([F:6])[F:7]
Reactant: C[Al](C)C
Reactant: COC(=O)C(C)(OCC(=O)c1cccc(Br)c1)C(F)(F)F
Agent: [Li]C
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Solvent: CCOCC
Product: COC(=O)C(C)(OCC(C)(O)c1cccc(Br)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[2-(3-bromo-phenyl)-2-oxo-ethoxy]-3,3,3-trifluoro-2-methyl-propionic acid methyl ester (6.6 g, 17 mmol) in toluene (120 ml) was added under argon at −78° C. a 2M solution of AlMe3 in heptane (17 ml, 34 mmol) and after stirring for 0.5 h at −78° C. a 1.6 M solution of MeLi in Et2O (21.3 ml, 34 mmol) over a period of 40 min. After stirring for 0.5 h at −78° C. the reaction mixture was added to a cold aqueous NaH2PO4 solution and was extracted with EtOAc. Combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel (toluene to toluene/EtOAc 10:1) to provide a diastereomeric mixture of the title compound as a yellow oil: TLC (toluene/EtOAc 10:1): Rf=0.34 and 0.37; HPLC RtH5=1.359 min; 1H NMR (360 MHz, CDCl3): δ 7.69 (m, 1H), 7.43 (m, 2H), 7.25 (t, 1H), 3.86 (s, 3H), 3.68 (m, 2H), 3.43 and 3.33 (s, 1H), 1.63 and 1.61 (s, 3H), 1.58 (s, 3H); ESIMS: 402, 404 [(M+NH4)+].
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[NH2:9].II.S(=O)(=O)(O)O.O[CH2:24][CH:25]([CH2:27]O)O>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:10]([CH:24]=[CH:25][CH:27]=[N:9]2)=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(N)cc1OCCN(C)C
Reactant: OCC(O)CO
Agent: II
Agent: O=S(=O)(O)O
Product: COc1cc2cccnc2cc1OCCN(C)C
Temperature: 180 °C
Yield: 8.1 %

Procedure:
3-(2-Dimethylaminoethoxy)-4-methoxyaniline (D14, 200 mg) was treated with glycerol (133 mg) and iodine (5 mg) and to this stirring mixture was added dropwise, concentrated sulphuric acid (267 mg). After the initial exothermic reaction had subsided, the mixture was heated at 180° C. for 1.5 hr. The reaction mixture was cooled and partitioned between 40% aqueous sodium hydroxide and ethyl acetate, the organic phase was dried (Na2SO4) and the solvent evaporated under reduced pressure to leave the title compound as a brown oil (19 mg, 51%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:32])[N:3]([CH2:4][C:5]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:6]=2[CH2:7][N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:9]3=[O:14])[CH3:2])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O)C(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and 3-chloro-phenyl-isocyanate (0.27 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and filtered. The resulting solid was rinsed with CH2Cl2 (5 mL) to give 3-(3-chloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea (0.68 g, 82%): mp 193-195° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.29 (99%); 1H NMR (DMSO-d6): δ 2.00-2.04 (m, 1H), 2.32-2.38 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.92 (m, 1H), 2.98 (s, 3H), 4.38 (d, J=17.3 Hz, 1H), 4.45 (d, J=17.3 Hz, 1H), 4.65 (s, 2H), 5.10-5.18 (dd, J=4.5, 13.2 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.46-7.41 (In, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.64-7.67 (m, 2H), 8.65 (s, 1H), 11.13 (s, 1H). 13C NMR (DMSO-d6) δ: 22.57, 31.19, 34.76, 46.27, 48.37, 51.60, 118.00, 119.08, 121.42, 121.77, 128.48, 129.85, 129.92, 131.93, 132.69, 133.62, 140.15, 142.04, 155.34, 168.00, 171.01, 172.84. Anal Calcd for C22H21ClN4O4: C, 59.93; H, 4.80; N, 12.71, Cl, 8.04. Found: C, 59.30; H, 4.66; N, 12.33, Cl, 8.36.