Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:31])[C:12]2[O:18][C:17]3[C:19]([Cl:27])=[CH:20][C:21]([NH:23][CH2:24][CH2:25]Cl)=[CH:22][C:16]=3[CH2:15][S:14](=[O:29])(=[O:28])[C:13]=2[CH:30]=1)=[O:8]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:31])[C:12]2[O:18][C:17]3[C:19]([Cl:27])=[CH:20][C:21]([NH:23][CH2:24][CH2:25][NH:4][CH:1]4[CH2:3][CH2:2]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:28])(=[O:29])[C:13]=2[CH:30]=1)=[O:8]
Reactant: NC1CC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNC3CC3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 5 h

Procedure:
Cyclopropylamine (0.819 g, 1.4 mmol) and tetrabutylammonium iodide (0.010 g, 0.027 mmol) were sequentially added with stirring to a solution of the carboxylic acid of Example 56k (0.59 g, 1.2 mmol) in dry methanol (10 mL). The reaction mixture was stirred at 110° C. for 5 h in an atmosphere of nitrogen. It was concentrated, treated with a methanolic HCl solution (15 mL) and refluxed for 2 h. The reaction mixture was concentrated, treated with an aqueous sodium bicarbonate solution to pH 7, water and extracted with n-butanol. The organic layer was washed with water, brine, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.120 g, (22%); 1H NMR (DMSO-d6): δ 0.20 (d, 2H, CH2), 0.40 (d, 2H, CH2), 2.10 (m, 1H, CH), 2.60 (s, 3H, CH3), 2.80 (t, 2H, CH2), 3.10 (d, 2H, CH2), 3.90 (s, 3H, OCH3), 5.15 (s, 2H, CH2), 6.10 (t, 1H, NH), 6.70 (s, 1H, Ar), 6.72 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.20 (s, 1H, Ar); MS: m/e (CI+) 451 (M+1).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([OH:29])[CH2:11][O: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:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:37]([O:44][C:45](Cl)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[CH2:1]([N:8]([C:45]([O:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:46])[CH2:9][CH:10]([OH:29])[CH2:11][O: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:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CNCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOCC(O)CN(Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
21.4 g of 3-benzylamino-1-hexadecyloxy-propan-2-ol are dissolved in 100 cc. of anhydrous chloroform. At first 5.4 g of triethylamine and then a solution of 9 g of chloroformic acid benzyl ester in 50 cc. of chloroform is added dropwise with cooling and the mixture is stirred for 3 hours. The chloroform solution is washed with 5% hydrocholoric acid and water, dried over sodium sulfate, evaporated and the residue is purified by column chromatography (silicic acid gel//chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[C:33]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:41][CH2:40][CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: NCCc1ccccc1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NCCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-phenyl-ethylamine
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[O:22]1[C:26]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[O:25][CH2:24][CH2:23]1>CO.C(Cl)Cl>[O:22]1[C:26]2([CH2:31][CH2:30][N:29]([CH2:1][C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]4[S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:28][CH2:27]2)[O:25][CH2:24][CH2:23]1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1[nH]c2ccc(CN3CCC4(CC3)OCCO4)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) with 1,4-dioxa-8-aza-spiro[4,5]decane (71.6 mg, 0.50 mmol) as described in General Procedure X to afford Iz (51.0 mg, 44.7%) as a tan solid, tlc Rf=0.35 (10% MeOH/CH2Cl2−0.20% Et3N), m/z obs=424 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]2)=[C:7]([OH:19])[C:6]=1[N+:20]([O-:22])=[O:21])=[O:4].[CH3:23]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.C[O+](C)C.F[B-](F)(F)F>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:17])([F:18])[F:16])=[N:12]2)=[C:7]([O:19][CH3:23])[C:6]=1[N+:20]([O-:22])=[O:21])=[O:4]
Reactant: COC(=O)c1cc2nc(C(F)(F)F)ccc2c(O)c1[N+](=O)[O-]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc2nc(C(F)(F)F)ccc2c(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.6 %

Procedure:
A solution of 5-Hydroxy-6-nitro-2-trifluoromethyl-quinoline-7-carboxylic acid methyl ester (1.5 g, 4.744 mmol) in methylene chloride is treated with N,N,N′,N′-Tetramethyl-1,8-naphthalendiamine (3.05 g, 14.232 mmol) and Trimethyloxonium-tetrafluorborate (2.11 g, 14.232 mmol) at 0-5° C. under argon. The reaction mixture is allowed to warm to room temperature with stirring. The reaction is complete after 2.5 hr as shown by TLC analysis. The reaction mixture is diluted with methylene chloride, and then washed successively with 2N aqueous hydrochloric acids, water, and brine. The organic phase is dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The residue (2.9 g) is purified by flash column chromatography, eluting with 3:1 hexane:ethyl acetate. This gives the title compound (1.2 g, 76%) as yellow crystals.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][C@H:14]([CH3:35])[C@H:15]([OH:34])[C@@H:16]([CH3:33])[CH:17]=[CH:18][CH2:19][CH2:20][C@@H:21]([OH:32])[C@@H:22]([CH3:31])[C@H:23]([OH:30])[C@@H:24]([CH3:29])[CH:25]=[CH:26][CH:27]=[CH2:28].O[Li].O.Cl>C1COCC1.O>[OH:34][C@H:15]([C@@H:16]([CH3:33])[CH:17]=[CH:18][CH2:19][CH2:20][C@@H:21]([OH:32])[C@@H:22]([CH3:31])[C@H:23]([OH:30])[C@@H:24]([CH3:29])[CH:25]=[CH:26][CH:27]=[CH2:28])[C@@H:14]([CH3:35])[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:36])=[O:2]
Reactant: C=CC=C[C@H](C)[C@@H](O)[C@H](C)[C@H](O)CCC=C[C@H](C)[C@@H](O)[C@@H](C)C=CCCCCCCCCC(=O)OC
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C=CC=C[C@H](C)[C@@H](O)[C@H](C)[C@H](O)CCC=C[C@H](C)[C@@H](O)[C@@H](C)C=CCCCCCCCCC(=O)O
Temperature: 60 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To an above solution 48 (8.0 mg) in THF-H2O (0.3 ml, 0.1 ml each) was added LiOH·H2O (1.3 mg) and the solution was warmed to 60° C. After stirring 6 h, 1N HCl (1 ml) was added and reaction mixture was extracted with CH2Cl2 (10 ml×2). After drying over MgSO4 and evaporation under vacuum, the crude was chromatographed on SiO2 (EtOAc/hexane 1:3) to yield 6.3 mg (81%) of the 49 as a colorless oil: IR (CHCl3) 3412, 2964, 2921, 2850, 2658, 1710, 1459, 1404, 1268, 971, 903 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.64 (ddd, J=16.7, 10.6, 10.0 Hz, 1H), 6.20 (apparent t, J=10.9 Hz, 1H), 5.54-5.46 (m, 1H), 5.42-5.36 (m, 2H), 5.32-5.18 (m, 4H), 3.88-3.84 (m, 1H), 3.48 (d, J=9.2 Hz, 1H), 3.23 (apparent t, J=5.7 Hz, 1H), 2.86-2.76 (m, 1H), 2.69-2.60 (m, 2H), 2.34 (t, J=7.4 Hz, 2H), 2.21-2.04 (m, 5H), 1.70-1.62 (m, 5H), 1.28 (br, 13H), 1.00 (d, J=6.8 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 180.6, 134.4, 133.8, 132.1, 132.0, 132.0, 131.3, 128.8, 119.1, 80.7, 79.2, 76.2, 37.6, 35.5, 34.6, 29.8, 29.7, 29.5, 29.2, 29.1, 29.0, 27.6, 24.8, 24.2, 22.8, 18.1, 16.7, 15.4, 14.2, 4.5; LRMS (API-ES) 515.3 (M+Na)+, 493 (M+H)+, 475 (M+H—H2O)+, 457 (M+H-2H2O)+, 242; [α]20D+33.0 (c 0.23, CHCl3).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].Cl[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1>C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)=[O:5])=[N:15][CH:16]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Clc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cn1)c1ccc(F)cc1
Yield: 8.5 %

Procedure:
Sodium hydride (Aldrich, 60% in oil, 13.03 g) was suspended in anhydrous THF (250 ml). 4-Fluoroacetophenone (15 g, 108.6 mmol) in anhydrous THF (100 ml) was added dropwise and the mixture heated to reflux for 1 h under nitrogen. The solution was cooled to 0° and 2,5 dichloropyridine (16.07 g) in anhydrous THF (75 ml) was added dropwise. The mixture was then heated to reflux overnight before being recooled to 0° and quenched with water dropwise (CAUTION! Hydrogen gas evolved, exothermic). The resulting reaction mixture was washed with brine and the organic phase dried and concentrated to give a mobile brown oil which was adsorbed onto silica gel and purified by Biotage chromatography with cyclohexane:ethyl acetate (40:1) as eluant. Combination and concentration of appropriate fractions gave the title compound as a yellow solid (2.31 g, 8.5%) which exists as a mixture of keto:enol forms, 1:2. NMR (CDCl3) δ 4.44 (2H, s, keto CH2); 6.0 (apparent 2H, s, enol CH═); 7.05-7.15 (10H, m); 7.26 (1H, d, J 9 Hz); 7.6-7.65 (apparent 3H, 2x dd, J 9 & 2 Hz); 7.8 (4H, dd, J 9 & 5 Hz); 8.35 (apparent 2H, J 3 Hz, N═CH); 8.52 (1H, J 3 Hz, N═CH) Tlc SiO2 cyclohexane:ethyl acetate (3:1) Rf 0.56 detection uv254.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:18]([N:20]1[C:32]2[CH:31]=[CH:30][C:29]([NH2:33])=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([NH:33][C:29]2[CH:30]=[CH:31][C:32]3[N:20]([CH2:18][CH3:19])[C:21]4[C:26]([C:27]=3[CH:28]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(NC(=O)CCCC(=O)O)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(NC(=O)CCCC(=O)Nc3ccc(C#N)cc3)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.7 %

Procedure:
To a solution of the compound obtained in Step 1 (200 mg, 0.97 mmol), 9-ethyl-9H-carbazol-3-amine (217 mg, 1.03 mmol) and DIEA (0.451 mL, 2.58 mmol) in DMF (6 mL) was added HATU (491 mg, 1.29 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 75% ethyl acetate/hexane) to give the title compound (229 mg, 0.540 mmol, 62.7%) as a white powder.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1)=O.[CH3:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:20]([N:19]([CH2:1][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1)[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1sc(C=O)cc1-c1ccccc1
Reactant: CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1sc(CN(C)Cc2ccccc2)cc1-c1ccccc1
Reaction time: 18 h
Yield: 94.3 %

Procedure:
To a solution of 172 (0.706 g, 2.87 mmol) in DCE (15 mL) was added N-Methylbenzylamine (0.388 mL, 3.01 mmol) and sodium triacetoxyborohydride (0.851 g, 4.01 mmol) and stirred for 18 hours. The reaction mixture was diluted in DCM and washed with a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude residue was purified by ISCO (40 g column, 0-30% ethyl acetate in hexanes) to yield compound 173 (951 mg, 94%) a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1COCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: C1CCNCC1
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
In THF (50 ml) was dissolved 4-nitrobenzylchloride (5.00 g), and piperidine (6.20 g) was added to the mixture. The reaction mixture was stirred at room temperature for 20 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1/2) to give 1-(4-nitrobenzyl)piperidine (6.41 g) as pale yellow oil. 1H NMR (200 MHz, CDCl3) δ: 1.38-1.70 (6H, m), 2.30-2.45 (4H, m), 3.55 (2H, s), 7.51 (2H, d, J=8.8 Hz), 8.17 (2H, d, J=8.8 Hz).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:20]([O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCN1CCNCC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCN1CCNCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
2-(Piperazin-1-yl)ethanol (1.000 g, 7.68 mmol) was dissolved in DCM (35.1 ml) and pyridine (0.932 ml, 11.52 mmol) followed by DMAP (0.094 g, 0.77 mmol) were added. tert-butylchlorodiphenylsilane (2.368 ml, 9.22 mmol) was added to the solution and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by column chromatography (ISCO, eluting with 10% MeOH/DCM) to give the title product (2.73 g, yield: 96%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[Cl:10].[NH2:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[Cl:10][C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[CH:6]=[CH:7][C:2]=1[O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][N:20]=[C:19]2[NH:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1
Reactant: OCc1ccc(F)c(Cl)c1
Reactant: Cn1ccc(N)n1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(CO)cc4Cl)cc23)n1

Procedure:
The compound of Example 131 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 4-fluoro-3-chlorobenzenemethanol, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].C1(CN)CCCCC1.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]([NH:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:44])=[CH:46][CH:47]=1
Reactant: NCCc1cccs1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(NCCc1cccs1)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-thiopheneethylamine to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(2-thiophen-2-ylethyl)benzamide was obtained (74%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.71 (d, J=7.9 Hz, 2H), 7.37 (d, J=7.9 Hz, 2H), 7.24-7.13 (m, 3H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.95 (dd, J=5.0, 3.5 Hz, 1H), 6.86 (d, J=3.5 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.51-6.46 (m, 1H), 6.46 (s, 1H), 6.42 (s, 1H), 4.97 (ABq, 2H), 4.83 (ABq, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.78-3.57 (m, 2H), 3.13 (t, J=6.2 Hz, 2H), 2.95 (t, J=8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 166.8, 161.8, 161.3, 141.7, 141.1, 139.2, 134.1, 132.5, 128.7, 127.5, 127.4, 127.0, 125.4, 123.9 (2C), 123.6, 119.9 (2C), 118.7, 109.0, 93.2, 80.5, 72.3, 57.6, 43.7, 41.2, 29.8, 28.9; MS (ES+) m/z 523.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([Br:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13](N)=[O:14]>>[Br:11][C:7]1[CH:6]=[C:3]2[C:2](=[C:9]([F:10])[CH:8]=1)[N:1]=[C:13]([OH:14])[N:12]=[CH:4]2
Reactant: NC(N)=O
Reactant: Nc1c(F)cc(Br)cc1C=O
Product: Oc1ncc2cc(Br)cc(F)c2n1
Temperature: 180 °C
Yield: 82.3 %

Procedure:
A stirred mixture of 2-amino-5-bromo-3-fluorobenzaldehyde (2.17 g, 10 mmol) and urea (9 g, 150 mmol) was heated at 180° C. for 2 h. LCMS showed the reaction was completed. The reaction mixture was cooled to RT, and the resulting precipitate was filtered and washed with water (500 mL*3). The moisture trapped was completely removed by the co-evaporation with toluene three times. The title compound (2 g, 83%) was obtained as a yellow solid. MS (ES+) C8H4BrFN2O requires: 242, 244. found: 243, 245 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1O.[CH3:10]I.[C:12](=[O:15])([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([O:5][CH3:10])[C:3]=1[O:15][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CI
Reactant: Oc1cccc(F)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(F)c1OC
Reaction time: 18 h
Yield: 93 %

Procedure:
After dissolving the 3-fluorocatechol (30 g, 0.234 mol) in dimethylformamide (400 ml), methyl iodide (32 ml, 0.515 mol) and potassium carbonate (80.7 g, 0.515 mol) were added while stirring on ice, and the stirring was continued at room temperature for 18 hours. Water (500 ml) was added and extraction was performed with diethyl ether (400 ml×2), and then after washing the combined organic layers with brine (400 ml) and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield the title compound as a light yellow liquid (34 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([C:26]12[CH2:37][CH2:36][CH2:35][C:33]3[C:34]1=[C:29]([CH:30]=[CH:31][CH:32]=3)[NH:28]C2=O)[C:24]#C.[CH2:39]([OH:41])[CH3:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:24]#[C:23][CH2:26][CH:37]3[CH:40]4[C:39](=[O:41])[NH:28][C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([C:34]=54)[CH2:35][CH2:36]3)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCC12CCCc3cccc(c31)NC2=O
Reactant: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(C#CCC3CCc4cccc5c4C3C(=O)N5)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was prepared by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with rac-2a,3,4,5-tetrahydro-2a-(2-propynyl)benz[cd]indol-2(1H)-one under the conditions described in Example 17. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate/ether to give colorless crystals of rac-2a-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin 2-yl]-2 propynyl}-2a,3,4,5-tetrahydrobenz[cd]indol-2(1H) one with m.p. 215°-217°.
Reaction SMILES: ClC1C=CC([C@H:8]2[C@H:13]([O:14]CC3C=CC=CC=3)[C@@H:12]([O:22]CC3C=CC=CC=3)[C@H:11]([O:30]CC3C=CC=CC=3)[C@@H:10]([CH2:38][O:39]CC3C=CC=CC=3)[O:9]2)=CC=1CC(=N)NN.C(C=O)=[O:53]>CCO>[CH2:38]([OH:39])[C@H:10]1[O:9][C:8](=[O:53])[C@H:13]([OH:14])[C@@H:12]([OH:22])[C@@H:11]1[OH:30]
Reactant: O=CC=O
Reactant: N=C(Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)NN
Solvent: CCO
Product: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
2-(2-Chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)acetimidohydrazide (compound 45, crude 1 g from step 1) in EtOH (30 ml) reacted with glyoxal (5 ml, 30% in water) at 0° C., and allowed to warm up at room temperature. After the reaction mixture was stirred for 3 hours, it was evaporated under reduced pressure to remove volatile compounds. The residue was purified with silica gel (Hx/EtOAc=⅓) to provided title compound (324 mg, 60% overall yield form intermediate 2).