Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:44][CH:45]1[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]1>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:44][CH:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reaction time: 0.17 h

Procedure:
To 4-amino-3-methoxybenzoic acid (1.064 g mg, 6.37 mmol) in dichloromethane (50 ml) was added DIPEA (2.22 ul, 12.74 mmol) and TBTU (2.25 g, 7.0 mmol) and the mixture stirred for 10 minutes. 4-amino-1-methylpiperidine (0.872 g, 7.65 mmol) was added and stirring continued for 16 hours. The resulting solid was filtered and dried under vacuum (1.04 g, 3.95 mmol, 62%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Temperature: 100 °C
Yield: 89.8 %

Procedure:
To a mixture of 2-chloro-N-cyclopropyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.3 g, 0.61 mmol), Pd(PPh3)2Cl2 (0.086 g, 0.122 mmol) and pyridine-4-ylboronic acid (0.165 g, 1.342 mmol) in dioxane (3 mL) was added a solution of Na2CO3 (0.2 g, 1.83 mmol) in water (1.5 mL). After degassing, the mixture was heated at 100° C. for 1.5 h. The mixture was purified by flash column chromatography (Hexane/EtOAc=1:1) to give 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.241 g).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[N:10]([CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[C:9]2[CH:21]=[C:22]([O:25]C)[CH:23]=[CH:24][C:8]=2[N:7]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:5][C:6]1[N:10]([CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[C:9]2[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:8]=2[N:7]=1
Reactant: CCCC1CC(=O)N(Cn2c(Cl)nc3ccc(OC)cc32)C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCC1CC(=O)N(Cn2c(Cl)nc3ccc(O)cc32)C1
Reaction time: 48 h
Yield: 35.6 %

Procedure:
Under argon, BBr3 (1M in CH2Cl2) (1.86 ml, 1.8645 mmol, 2 eq) is added drop wise to a solution of 1-[(2-chloro-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one 305 (0.3 g, 0.9322 mmol, 1 eq) in dry CH2Cl2 (20 ml). After 48 hours at room temperature, saturated aqueous solution of NaHCO3 (20 ml) is added. The aqueous layer is extracted with CH2Cl2 (3×20 ml) then the combined organic layers are dried on anhydrous MgSO4, filtered off and evaporated under reduced pressure. The remaining pale yellow solid is recrystallized in MeCN/H2O (9/1) to yield 102 mg of 1-[(2-chloro-6-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one 320 as a white solid.
Reaction SMILES: [C:1]1([CH:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]12[O:24][CH:23]1[CH2:22][CH2:21][CH2:20][CH2:19]2>C(O)C>[O:24]=[C:23]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[N:14]1[CH2:13][CH2:12][C:11]2([C:10](=[O:17])[NH:9][CH2:8][CH:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:16][CH2:15]1
Reactant: C1CCC2OC2C1
Reactant: O=C1NCC(c2ccccc2)C12CCNCC2
Solvent: CCO
Product: O=C1CCCCC1N1CCC2(CC1)C(=O)NCC2c1ccccc1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A suspension of rac-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one (13.10 g, 56.9 mmol) and 7-oxa-bicyclo[4.1.0]heptane (5.58 g, 56.9 mmol) in ethanol (250 mL) was heated under reflux for 3 days. After cooling to room temperature the mixture was filtered and the filtrate evaporated to afford the title compound (18.14 g, 97%) which was obtained as off-white solid. MS: m/e=329.3 (M+H).
Reaction SMILES: [Si:1]([CH:5]=[N+:6]=[N-:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[CH:29]=[N:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>CCOCC>[F:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[CH:29]=[N:28][CH:27]=[CH:26][C:23]=1[C:24]1[N:25]=[N:7][NH:6][C:5]=1[Si:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#Cc1ccncc1Nc1ccc(I)cc1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1[nH]nnc1-c1ccncc1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a solution of TMSdiazomethane (2 M, 90 μL, 0.18 mmol) in ether (2 mL) at 0° C., was added butyl lithium (2.5 M, 72 μL, 0.18 mmol) dropwise. The mixture was stirred for 20 min at 0° C. 3-[(2-fluoro-4-iodophenyl)amino]isonicotinonitrile (50 mg, 0.15 mmol) was then added into the solution. The reaction was allowed to warm to room temperature and proceed for three days. The mixture was diluted with ether and washed with saturated ammonium chloride solution, water, and dried over solid Na2SO4. The organic phase was concentrated, and the resulting residue was applied to chromatography in silica gel to give the desired product in 40% yield (27 mg). LC/MS [Method A: rt: 0.40 min; m/z: 454 (M+1)].
Reaction SMILES: [C:1]([N:3]=[C:4]([S-:6])[S-:5])#[N:2].[K+:7].[K+].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.CO>O>[C:1]([N:3]=[C:4]([S-:6])[S:5][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=1)#[N:2].[K+:7]
Reactant: N#CN=C([S-])[S-]
Reactant: ClCc1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CN=C([S-])SCc1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
A mixture of 80 g of dipotassium N-cyano-dithioimidocarbonate, 64.9 g of p-chlorobenzyl chloride, 400 ml of methanol and 400 ml of water was stirred for 5 hours and the solvents were evaporated. The residue was crystallized from ethanol to obtain monopotassium S-p-chlorobenzyl N-cyano-dithioimidocarbonate with a melting point of 250° C (dec).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.Br[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=1[Cl:20].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=2[Cl:20])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: COc1cc(Br)c(Cl)cc1Cl
Reactant: Cc1cnc(Cl)nc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(Cl)ncc2C)c(Cl)cc1Cl

Procedure:
To a solution of 2-chloro-5-methylpyrimidin-4-amine (44.8 mg, 0.31 mmol) in 1,4-dioxane (20 mL) was added 1-bromo-2,4-dichloro-5-methoxybenzene (96 mg, 0.37 mmol), Cs2CO3 (408 mg, 1.25 mmol), Pd2(dba)j (37 mg, 0.04 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 70 mg, 0.12 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1×100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo. The crude product was used for next reaction without purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([NH2:9])=[O:8].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:10]([NH:9][C:7]([C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)[C@@H]1CCCCN1
Reactant: BrCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.6 %

Procedure:
To a suspension of 9.0 g (70.2 mmol) of (S)-piperidine-2-carboxamide (prepared by the method of Geotz Hardtmann, William Houlihan and Rudolf Giger, U.S. Pat. No. 4,760,065) in 100 mL of methylene chloride was added 24.0 g (140.4 mmol) of benzyl bromide and 7.2 g (70.2 mmol) of triethylamine. The mixture was stirred at room temperature for 24 h and washed with 1N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and solvent was removed at reduced pressure. The residue was purified by silica gel chromatography using hexane:ethyl acetate (1:1) as eluent to give (S)-N-benzyl-piperidine-2-carboxamide (12.2 g, 80%), mp 103°-104° C., specific rotation=-90.7° (c=2.5, ethanol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@@H:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N:30]=[C:31]=[O:32])(C)C>CC(O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@@H:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:31]([NH2:30])=[O:32])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1cnc(CN(CCCCN)[C@H]2CCCc3cccnc32)c(C)c1
Solvent: CC(C)O
Product: Cc1cnc(CN(CCCCNC(N)=O)[C@H]2CCCc3cccnc32)c(C)c1
Yield: 29.7 %

Procedure:
To a solution of (S)-N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (103 mg, 0.30 mmol) in 2-propanol (1.5 mL) was added trimethylsilyl-isocyanate (50 μL, 0.378 mmol). The resultant solution was stirred at room temperature overnight then concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH) provided 34 mg (29%) of the free base of the title compound as a white foam. Using General Procedure D: Conversion of the white foam to the HBr salt gave COMPOUND 367 (47 mg, 81%) as a white solid. 1H NMR (D2O) δ 1.15-1.29 (m, 4H), 1.75-1.91 (m, 1H), 2.06-2.22 (m, 2H), 2.41-2.50 (m, 8H), 2.66-2.74 (m, 1H), 2.90-3.03 (m, 4H), 4.19 (d, 1H, J=17.7 Hz), 4.38 (d, 1H, J=17.7 Hz), 4.50 (dd, 1H, J=10.5, 5.1 Hz), 7.88 (dd, 1H, J=7.8, 6.0 Hz), 8.23 (s, 1H), 8.36 (d, 1H, J=7.8 Hz), 8.46 (s, 1H), 8.62 (d, 1H, J=5.1 Hz); 13C NMR (D2O) δ 16.97, 17.51, 20.49, 20.62, 25.43, 27.23, 27.83, 39.41, 52.08, 52.46, 61.55, 125.80, 136.35, 137.32, 137.59, 139.28, 140.55, 148.02, 149.13, 151.35; ES-MS m/z 382 (M+H). Anal. Calcd. For C22H31N5O.3.0HBr.1.8H2O: C, 40.24; H, 5.77; N, 10.66; Br, 36.50. Found: C, 40.22; H, 5.63; N, 10.62; Br, 36.50.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH:20]([O:23]C1C=CC=C2C=1NC=C2)([CH3:22])[CH3:21]>>[CH:20]([O:23][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2)([CH3:22])[CH3:21]
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: CC(C)Oc1cccc2cc[nH]c12
Product: CC(C)Oc1cccc2cc(B3OC(C)(C)C(C)(C)O3)[nH]c12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-isopropoxy-1H-indole.
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:57]3[C:52](=[N:53][CH:54]=[C:55]([F:58])[CH:56]=3)[NH:51][CH:50]=2)=[CH:45][C:44]=1[NH:59][C@H:60]1[CH2:65][CH2:64][CH2:63][C@@H:62]([NH2:66])[CH2:61]1>C1COCC1>[C:1]([C:3]1([C:6]([NH:66][C@@H:62]2[CH2:63][CH2:64][CH2:65][C@H:60]([NH:59][C:44]3[CH:45]=[C:46]([C:49]4[C:57]5[C:52](=[N:53][CH:54]=[C:55]([F:58])[CH:56]=5)[NH:51][CH:50]=4)[CH:47]=[CH:48][C:43]=3[F:42])[CH2:61]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N[C@@H]1CCC[C@H](Nc2cc(-c3c[nH]c4ncc(F)cc34)ccc2F)C1
Reactant: N#CC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#CC1(C(=O)N[C@@H]2CCC[C@H](Nc3cc(-c4c[nH]c5ncc(F)cc45)ccc3F)C2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-cyano-1-cyclopropane-carboxylic acid (0.058 g, 0.527 mmol) in THF at room temperature was added HATU (0.200 g, 0.527 mmol) followed by N,N-diisopropylethylamine (0.334 mL, 1.91 mmol). The solution was stirred for 10 minutes. (1S,3R)—N1-(2-fluoro-5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclohexane-1,3-diamine, 44e, (0.200 g, 0.584 mmol) was then added and solution stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and purified via silica gel chromatography (30-60% Ethyl Acetate/hexanes) to give 80 mg of 871 as off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>N1C=CC=CC=1>[CH3:23][O:22][C:16]1[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:2]([O:1][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1ccc(C=CC(=O)c2c(O)cc(OC)cc2OC)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)c2c(OC)cc(OC)cc2OC(=O)c2cccnc2)cc1
Yield: 82.4 %

Procedure:
A solution of 2'-hydroxy-4,4',6'-trimethoxychalcone (1 g) and hydrochloride of nicotinoyl chloride (0.6 g) in 20 ml of pyridine was stirred at room temperature for 4 hours. After removal of the solvent followed by addition of saturated aqueous sodium bicarbonate (50 ml) to the residue, the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over Na2SO4 and evaporated under reduced pressure to give an oily residue. Crystallization from methanol/hexane gave 1.1 g (83% yield) of 2',4,4'-trimethoxy-6'-(nicotinoyloxy)chalcone as pale yellow needles; m.p. 55°-60° C.
Reaction SMILES: CC(C([O:6][CH:7]1[C@@:12]2(C)[C:13]([CH3:15])(C)[C@H:9]([CH2:10][CH2:11]2)[CH2:8]1)=O)=C.[CH3:17][CH:18]([CH2:20][C:21]([CH3:23])=O)[CH3:19]>>[CH2:7]([OH:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:15][CH2:12][CH2:7][CH2:8][CH2:9][CH2:23][CH2:21][CH2:20][CH:18]([CH3:19])[CH3:17]
Reactant: C=C(C)C(=O)OC1C[C@H]2CC[C@]1(C)C2(C)C
Reactant: CC(=O)CC(C)C
Product: CC(C)CCCCCCCCCCCCCCCO
Temperature: 65 °C

Procedure:
In a second step, a 3-necked reaction flask equipped with a thermometer, Dean Stark condenser, mechanical stirrer, heating mantle and nitrogen inlet, was charged with 60.7 g of the iBMA oligomer solution as prepared above (30 meq.), 8.1 g isostearylacohol (30 meq.) and 138.4 g MIBK. 50 g MIBK/H2O azeotrope was distilled off via the Dean Stark condenser. After replacing the Dean Stark by a normal reflux condenser, the mixture was cooled to 65° C. and 30.3 g MDI (240 meq.) were added. The reaction mixture was heated for 2 hours at 75° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Sn](C)(C)C>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1
Reactant: C[Sn](C)(C)c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3c(F)cccc3F)cc3c1N2CCS3
Yield: 76.1 %

Procedure:
The tert-butyl(6bR,10aS)-5-(2,6-difluorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (288 mg, 76%) was prepared via coupling of tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (0.350 g, 0.851 mmol) with 2,6-difluorophenyltrimethyl stannane (0.707 g, 2.553 mmol) using the procedure described in Example 447 Step G.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9]([C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH2:22]([O:24][C:25](=[O:37])[CH:26]([OH:36])[CH:27]([NH3+:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:23]>>[OH:36][CH:26]([CH:27]([NH:35][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[N:20][C:12]=1[N:9]1[CH:10]=[CH:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:25]([O:24][CH2:22][CH3:23])=[O:37]
Reactant: O=C(O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.1 starting from 2-(3-phenyl-1H-pyrazol-1-yl)nicotinic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride. ESI-MS [M+H]+=471.2
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.O.NN.NC(C1C=CC=CC=1Cl)C1C=CC([Cl:36])=CC=1N1C(C)=NN=C1C1CC1>C(O)COCCO>[NH2:8][CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])[C:6]1[CH:24]=[CH:2][C:3]([Cl:36])=[CH:4][C:5]=1[N:11]1[C:10]([CH3:9])=[N:14][N:13]=[C:12]1[CH2:15][OH:16]
Reactant: Cc1nnc(C2CC2)n1-c1cc(Cl)ccc1C(N)c1ccccc1Cl
Reactant: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: OCCOCCO
Solvent: O
Product: Cc1nnc(CO)n1-c1cc(Cl)ccc1C(N)c1ccccc1Cl

Procedure:
A mixture of 10.776 g. 8-chloro-6-(o-chlorophenyl)-1-hydroxymethyl-4H-s-triazolo[4,3-a] [1,4]benzodiazepine (111) (30.0 mmoles) and 7.50 ml. of hydrazine hydrate in 60 ml. of diethylene glycol is heated to 150°-160° C. for about 18 hours. The reaction is then quenched in a cold aqueous 5% sodium hydroxide solution and the product extracted with chloroform. The extracts thus obtained are dried over anhydrous magnesium sulfate and concentrated in vacuo to give 13.0 g. of oil which is crystallized from methanol/ethyl acetate to give 1.93 g. of a mixture of the A and B isomers (ratio 81/19) of 4-[α-amino-4-chloro-α-(o-chlorophenyl)-o-tolyl]-3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazole (I) m.p. 205°-215° C. The mixture thus obtained is recrystallized from the same solvent mixture to give 0.76 g. of 4-[α-amino-4-chloro-α-(o-chlorophenyl)-o-tolyl]-o-tolyl]-3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazole (I), (isomer A) melting at 218° - 223° C., and having infrared (mull) spectral absorptions at 3330, 3240, 3150, 3060, 2680, 1600, 1570, 1530, 1515 and 1485 cm-1.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[N:11][CH2:12][C:13]3[N:14]([C:15]([CH2:18]Cl)=[N:16][N:17]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[I-].[K+].[CH2:29]([NH2:32])[CH:30]=[CH2:31]>O1CCCC1>[CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[N:11][CH2:12][C:13]3[N:14]([C:15]([CH2:18][NH:32][CH2:29][CH:30]=[CH2:31])=[N:16][N:17]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCSc1cccc2c1C(c1cccc(Cl)c1)=NCc1nnc(CCl)n1-2
Reactant: C=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1cccc(SCC)c1C(c1cccc(Cl)c1)=NC2

Procedure:
In the manner given in Example 31, 7-(ethylthio)-1-(chloromethyl)-6-(m-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4] benzodiazepine, potassium iodide and allylamine in tetrahydrofuran are reacted to give 7-(ethylthio)-1-[(allylamino)methyl]-6-(m-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][C:11]#[N:12].[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3[CH:28]=[N:29][N:30]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:31]=34)[N:22]=2)[CH2:15]1>C(O)C>[C:11]([CH2:10][C:9]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3[CH:28]=[N:29][N:30]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:31]=34)[N:22]=2)[CH2:15]1)=[O:8])#[N:12]
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: N#Cc1ccn2ncc(-c3nccc(N[C@@H]4CCCNC4)n3)c2c1
Solvent: CCO
Product: N#CCC(=O)N1CCC[C@@H](Nc2ccnc(-c3cnn4ccc(C#N)cc34)n2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.3 %

Procedure:
3-[(2,5-Dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (prepared as described in BE875054(A1), 40 mg, 0.20 mmol) was added to a stirred solution of 3-{4-[(3R)-piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-carbonitrile (Preparation 7b, 60 mg, 0.16 mmol) in ethanol (1.2 mL) and the mixture was stirred at ambient temperature for 20 hours. The solvent was then removed under reduced pressure and the residue was taken-up in a mixture of dichloromethane and 4% aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried (MgSO4) and the solvent evaporated in vacuo. The crude product was purified by flash chromatography (chloroform to 40:1 chloroform/methanol) to give the title compound (20 mg, 27%) as a solid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][C:9]#[N:10])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:18][C:5]1[C:6]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([CH2:8][C:9]#[N:10])[C:2]([F:1])=[CH:3][CH:4]=1
Reactant: N#CCc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#CCc1c(F)ccc(N)c1Nc1ccccc1
Yield: 55.6 %

Procedure:
(6-Fluoro-3-nitro-2-phenylaminophenyl)acetonitrile (463 mg, 1.70 mmol), iron powder (194 mg, 3.41 mmol), and ammonium chloride (263 mg, 5.12 mmol) in methanol (10 mL) and water (3 mL) were heated at 90° C. for 1 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as brown solid (228 mg, 55%). 1H NMR 400 MHz δ (CDCl3): 7.23-7.17 (2H, m), 6.95 (1H, t, J=8.9 Hz), 6.83 (1H, tt, J=7.4, 1.0 Hz), 6.77 (1H, dd, J=8.9, 5.5 Hz), 6.61-6.56 (2H, m), 5.12 (1H, br s), 3.79 (2H, br s), 3.59 (2H, d, J=1.2 Hz).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:15]C)=[CH:6][C:7]2[O:12][CH2:11][CH2:10][CH:9]([CH3:13])[C:8]=2[CH:14]=1)(=[O:3])[CH3:2].B(Cl)(Cl)Cl>C(Cl)Cl>[C:1]([C:4]1[C:5]([OH:15])=[CH:6][C:7]2[O:12][CH2:11][CH2:10][CH:9]([CH3:13])[C:8]=2[CH:14]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1C(C)=O)C(C)CCO2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1cc2c(cc1O)OCCC2C
Temperature: 25 °C
Yield: 67.7 %

Procedure:
The product of step (d) (57.4 g) in dry methylene chloride (500 ml) was treated with boron trichloride (61 g) in dry methylene chloride (150 ml) at -70° C. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature during 1 hour. The reaction mixture was poured into water and the methylene chloride layer was separated, washed with water and dried. Evaporation of the solvent left 55.7 g of crude product; this was dissolved in ether and extracted several times with a sodium hydroxide solution. The basic extracts were acidified and the precipitated product extracted with ether, which was washed with water and dried. Evaporation of the solvent gave 36.4 g of product mp 91°-96°. A recrystallisation from ethanol gave the title compound, mp 104°-105°.