Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)([O-:24])=[O:23].[Na+]>>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([S:31]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:33])=[O:32])=[CH:29][CH:30]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(S(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc([N+](=O)[O-])cc4)cc3c2C1
Yield: 25 %

Procedure:
The product of Example 29, step B and sodium 4-nitrobenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) provided tert-butyl 8-(4-nitrophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (96 mg, 25%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.08 (s, 1H), 7.83 (dd, J=8.7, 1.8 Hz, 1H), 7.77-7.72 (m, 1H), 7.65 (dt, J=7.8, 2.1 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.50-7.44 (m, 1H), 7.25-7.20 (m, 1H), 4.58 (s, 2H), 3.84 (t, J=5.7 Hz, 2H), 2.91-2.82 (m, 2H), 1.55 (s, 9H).
Reaction SMILES: [CH3:1][O:2][B:3]([O:13][CH3:14])[C:4]1[CH:5]=[N:6][C:7]([CH2:10][CH2:11][CH3:12])=[N:8][CH:9]=1.O[CH2:16][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C)CO>CO>[CH2:10]([C:7]1[N:6]=[CH:5][C:4]([B:3]2[O:2][CH2:1][CH:16]([CH2:17][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][O:13]2)=[CH:9][N:8]=1)[CH2:11][CH3:12]
Reactant: CCCCCCCC(CO)CO
Reactant: CCCc1ncc(B(OC)OC)cn1
Solvent: CO
Product: CCCCCCCC1COB(c2cnc(CCC)nc2)OC1

Procedure:
20 g of dimethoxy-(2-propylpyrimidin-5-yl)-borane (obtained from 2-propylpyrimidin-5-ylmagnesium chloride and trimethoxyborane) and 30 g of 2-hydroxymethylnonan-1-ol are heated at 100° for 12 hours, the methanol formed being removed continuously by distillation. When the reaction is complete, excess nonanol is removed under reduced pressure, and 2-(2-propylpyrimidin-5-yl)-5-heptyl-1,3,2-dioxaborinane is obtained.
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH:29](=O)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C>>[CH2:29]([C:21]1[C:20]2[CH:19]=[CH:18][C:17]([F:22])=[CH:16][C:15]=2[N:14]=[C:13]2[C:23]3[N:10]([CH2:11][C:12]=12)[C:9](=[O:26])[C:8]1[CH2:7][O:6][C:5](=[O:27])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:28])[C:25]=1[CH:24]=3)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Reactant: CCCCCCCCCCC=O
Product: CCCCCCCCCCc1c2c(nc3cc(F)ccc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 2 is treated with undecanal according to a procedure similar to Stage 13e in order to produce the expected solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=3)=[CH:27][CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)cc1
Product: CC(C)(C)OC(=O)N1CCCC(OCc2ccc(-c3ccc(Cl)cc3)cc2)C1
Yield: 83.6 %

Procedure:
Using 1-(tert-butoxycarbonyl)-3-hydroxypiperidine (403 mg, 2.00 mmol) and 4′-chloro-4-chloromethylbiphenyl (474 mg, 2.00 mmol), the same procedure was followed as in Step 6a of Example 6 to give 672 mg (84%) of the desired compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23](=[O:28])[C:24]([NH:26][NH2:27])=[O:25])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.[C:31](C1NC=CN=1)(C1NC=CN=1)=[O:32]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:24]3[O:25][C:31](=[O:32])[NH:27][N:26]=3)=[O:28])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)C(=O)NN
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.1 %

Procedure:
To a solution of (R)-ethyl 4-(5′-fluoro-2′-methoxy-[1,1′-biphenyl]-4-yl)-3-(2-hydrazinyl-2-oxoacetamido)butanoate (4.7 g, 11 mmol) in THF (115 mL) was added carbonyl diimidazole (2.4 g, 14 mmol) and the reaction mixture was stirred at room temperature for 24 hours then concentrated to a yellow oil than was purified by silica gel chromatography (40-45% ethyl acetate/hexane) to afford (R)-ethyl 4-(5′-fluoro-2′-methoxy-[1,1′-biphenyl]-4-yl)-3-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)butanoate 4.25 g (84%). LCMS Method 1 retention time 1.57 min ES+ M+H(+) 443.8; LCUV Method 2 retention time 7.44 min; 1H NMR (400 MHz, MeOH-d) δ ppm 7.44 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 7.03-7.05 (m, 3H), 4.67 (t, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.76 (s, 3H), 2.96 (d, J=6.8 Hz, 2H), 2.66 (d, J=6.8 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:11][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N:23]3[CH:27]=[N:26][N:25]=[CH:24]3)[CH:21]=2)[NH:16][CH:15]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:29]1([CH2:28][N:10]([CH2:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([N:23]4[CH:27]=[N:26][N:25]=[CH:24]4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:9][CH2:8][NH2:7])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NCCN(CCCc1c[nH]c2ccc(-n3cnnc3)cc12)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCN(CCCc1c[nH]c2ccc(-n3cnnc3)cc12)Cc1ccccc1

Procedure:
A solution of 2-[(phenylmethyl)(3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl)amino]ethyl carbamic acid tert-butyl ester (440 mg, 0.93 mmol) and trifluoroacetic acid (3 ml) in CH2Cl2 (20 ml) was stirred at room temperature for 5 h. After this time the solvent was evaporated and the residue azeotroped with CH2Cl2 (20 ml) and toluene (20 ml). The residue was partitioned between CH2Cl2 (2×30 ml) and K2CO3 (10%; 20 ml). the combined organic layers were dried (NaSO4) and evaporated. The amine (287 mg, 83%, which was isolated as a colourless foam was used without further purification. 1H NMR (250 MHz, CDCl3 +d4 -MeOH) δ1.83-1.99 (2H, m), 2.44-2.59 (4H, m), 2.61-2.79 (4H, m) 3.58 (2H, s), 7.07 (1H, s), 7.11 (1H, dd, J=8.6 and 2.1 Hz), 7.20-7.32 (5H, m), 7.48 (1H, d, J=8.6 Hz), 7.51 (1H, d, J=2.1 Hz), 8.49 (2H, s).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[C:21]([O:22][CH3:23])=[CH:20][C:15]2[NH:16][C:17](=[O:19])[S:18][C:14]=2[CH:13]=1>>[CH3:23][O:22][C:21]1[C:12]([NH:11][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:13][C:14]2[S:18][C:17](=[O:19])[NH:16][C:15]=2[CH:20]=1
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: Clc1ncnc2[nH]ccc12
Product: COc1cc2[nH]c(=O)sc2cc1Nc1ncnc2[nH]ccc12

Procedure:
20 mg (130 μmol) 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CAS-No. 3680-59-1) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 8.0 mg (19%) of the title compound.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]3[CH:20]=[CH:21][CH:22]=[C:11]3[CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[Cl:29][C:30]([Cl:35])([Cl:34])[C:31](Cl)=[O:32].O>O1CCOCC1>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]3[C:20]([C:31](=[O:32])[C:30]([Cl:35])([Cl:34])[Cl:29])=[CH:21][CH:22]=[C:11]3[CH2:10]2)=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Temperature: 25 °C

Procedure:
10-(1,1′-Biphenyl-4-ylcarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step A (1.822 g; 0.005 mol) was dissolved in 50 mL of 1,4-dioxane to which was then added 0.946 g (0.0052 mol) of trichloroacetyl chloride. The reaction solution was heated under reflux with stirring over night, cooled to room temperature and then poured into 250 mL of water. Recrystallization of the crude material from ethanol provided a solid, m.p. 197-198° C.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](O)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:20])=O.CN(C)C=O>>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([Cl:20])=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (600 mg, 2.5 mmol) in thionyl chloride (5400 L, 7.4 mmol) was added N,N-dimethylformamide (60 L, 0.60 mmol). The reaction mixture was stirred at room temperature for one hour. Excess thionyl chloride and N,N-dimethylformamide were removed in vacuo and the resulting acid chloride was used without further purification.
Reaction SMILES: C(OC([O:7][CH2:8][CH3:9])C=O)C.[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2C=1C=[N:18][CH:17]=[CH:16]2>>[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:9]=1[C:8](=[O:7])[NH:18][CH:17]=[CH:16]2
Reactant: Brc1cccc2ccncc12
Reactant: CCOC(C=O)OCC
Product: O=c1[nH]ccc2cccc(Br)c12

Procedure:
The isoquinolin-8-yl system can be prepared from the appropriately substituted benzylamine by cyclocondensation with diethoxy-acetaldehyde (see, for example, K. Kido and Y. Watanabe, Chemical & Pharmaceutical Bulletin, 35(12), 4964-6; 1987). Alternatively 8-bromo-isoquinoline (prepared by the method of F. T. Tyson, J.A.C.S., 1939, 61, N. Briet et al., Tetrahedron (2002), 58(29), 5761-5766 or W. D. Brown, et al., Synthesis (2002), (1), 83-86. 183 can be subjected to N-oxidation and rearrangement to give 8-bromo-2H-isoquinolin-1-one. This can be N-methylated to give 8-bromo-2-methyl-2H-isoquinolin-1-one, an appropriate intermediate for the 2-methyl-1-oxo-1,2-dihydroisoquinolin-8-yl system.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:3]([OH:22])[CH2:4][N:5]1[C@H:14]([C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1.[CH2:30]([O:37][C:38]([NH:40][C@H:41]([C:46](O)=[O:47])[CH2:42][C:43](=[O:45])[NH2:44])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[CH2:30]([O:37][C:38]([NH:40][C@H:41]([C:46]([NH:1][C@@H:2]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@H:3]([OH:22])[CH2:4][N:5]1[C@H:14]([C:15]([NH:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][C@H:12]2[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1)=[O:47])[CH2:42][C:43](=[O:45])[NH2:44])=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
A solution of 561 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 372 mg of N-(benzyloxycarbonyl)-L-asparagine in 20 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 189 mg of hydroxybenzotriazole, 161 mg of N-ethylmorpholine and 317 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 16 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 434 mg of 2-[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS )-isoquinoline-3(S)-carboxamide as a white solid from methanol/diethyl ether: MS: m/e 650 [M+H]+.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.C([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:31]#[C:32][CH3:33])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]([CH2:31][CH2:32][CH3:33])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:24]=1
Reactant: CC#CC(CC(=O)OC)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CCCC(CC(=O)OC)c1ccc(O)cc1
Reaction time: 2 h
Yield: 0.8 %

Procedure:
To a 500 mL parr hydrogenater flask with ethyl acetate (5 mL) and quinoline (0.117 g, 1.4 mmol), was added methyl 3-[4-(benzyloxy)phenyl]hex-4-ynoate (0.2 g, 65.0 mmol) and 10% Pd/C (0.015 g) under N2 atmosphere. The RM was hydrogenated for 2 h. The RM was diluted with ethyl acetate (10 mL), filtered the catalyst through celite and evaporated to dryness under reduced pressure. The crude was purified by flash column chromatography on silica gel (100/200 mesh), to give the product (0.11 g, yield: 76.38%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([CH3:15])[CH:6]=1)(=[O:3])[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>[OH-].[Na+].CC(C)=O>[CH3:15][C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][C:8]=1[S:11]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:13])=[O:12]
Reactant: C1CCNC1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCCC2)c(C)c1
Temperature: 25 °C

Procedure:
1.45 g of 4-acetylamino-2-methyl-benzenesulphonyl chloride (5.85 mmol) at 0° C. are suspended in 19 ml sodium hydroxide solution (1 M) and then 0.51 ml pyrrolidine (6.47 mmol), dissolved in 9 ml acetone, are added dropwise within half an hour. The solution is heated to ambient temperature overnight and then acidified with hydrochloric acid (2 M). The suspension is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down. A brown oil remains.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]=1Br)=[O:5])[CH3:2].C([Li])(C)(C)C.CN([CH:34]=[O:35])C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]=1[CH:34]=[O:35])=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (I-2d, 4.4 g, 0.01 mmol) in anhydrous THF (100 ml) at −78° C. was slowly added tert.-butyl lithium (13 ml of 1.7 M solution in pentane, 0.22 mol). After 1 hour, DMF (7.7 ml, 0.1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 2.5 hours, quenched with sat'd aq. NH4Cl (10 ml), allowed to slowly warm to room temperature, and finally poured into sat'd aq. NaCl. The aqueous solution was extracted with Et2O (3×) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified via flash chromatography using a solvent gradient of 1:3 EtOAc/hexanes to 1:1 EtOAc/hexanes to give the desired product I-2e as a pale yellow amorphous glass (2.0 g): +APCI MS (M+1) 389.2; 1H NMR (CD2Cl2) δ 1.41 (3H, t), 4.45 (2H, q), 7.09–7.14 (2H, m), 7.24–7.39 (7H, m), 10.50 (1H, s).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Reactant: Cc1cccc(N)c1
Product: CCOC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 91.2 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.2 g, 0.45 mmol) obtained in Example 128, step 2 and m-toluidine (0.073 g, 0.68 mmol), the title compound (0.21 g, 92%) was obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([Br:22])[N:19]=[C:20](Br)[C:15]4=[N:14][C:13]=3[CH2:23][OH:24])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH3:26][CH:27]([CH3:30])[CH2:28][NH2:29].C1(C)C=CC=CC=1>CN(C)C=O>[Br:22][C:18]1[N:19]=[C:20]([NH:29][CH2:28][CH:27]([CH3:30])[CH3:26])[C:15]2[N:16]([C:12]([C:9]3[CH:8]=[CH:7][C:6]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:25])=[CH:11][CH:10]=3)=[C:13]([CH2:23][OH:24])[N:14]=2)[CH:17]=1
Reactant: CC(C)CN
Reactant: O=C(NC1CC1)c1ccc(-c2c(CO)nc3c(Br)nc(Br)cn23)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)CNc1nc(Br)cn2c(-c3ccc(C(=O)NC4CC4)cc3)c(CO)nc12
Temperature: 23 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of 50 mg (107 μmol) N-cyclopropyl-4-[6,8-dibromo-2-(hydroxymethyl)imidazo[1,2-a]pyrazin-3-yl]benzamide in 0.71 mL N,N-dimethylformamide were added 32 μL 2-methylpropan-1-amine and the mixture was stirred at 23° C. for 3 hours. Toluene was added and the solvents removed. The residue was purified by chromatography to give 40.7 mg (83%) of the title compound. 1H-NMR (300 MHz d6-DMSO): δ=8.52 (1H, d), 8.12 (1H, t), 7.95 (2H, d), 7.68 (2H, d), 7.50 (1H, s), 5.18 (1H, t), 4.46 (2H, d), 3.23 (2H, m), 2.85 (1H, m), 2.00 (1H, m), 0.87 (6H, m), 0.68 (2H, m), 0.55 (2H, m) ppm. UPLC-MS: RT=1.18 min; m/z 459.4 [MH+]; required MW=458.4.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[N:8]=1)=O.[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32]N)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1>>[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([N:32]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: NNc1ccc2c(c1)OCCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(O)c2)ccc1=O
Product: O=c1ccn(-c2cccc(O)c2)nc1-c1ccnn1-c1ccc2c(c1)OCCO2

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-hydroxyphenyl)-1H-pyridazin-4-one (A-17) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-hydrazine according to the method described for example 91. MS: M=389.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH:5]=[CH:6][S:7]([NH2:10])(=[O:9])=[O:8].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH:5]=[CH:6][S:7]([NH:10][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:17]([O:16][CH3:15])[CH:18]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: NS(=O)(=O)C=Cc1ccc(Cl)c(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(=O)NS(=O)(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1OC
Yield: 70 %

Procedure:
A mixture of 3,4-dichlorostyrylsulfonamide (12.6 g., 0.05 mole) and 3,4-dimethoxybenzoyl chloride (11.0 g., 0.055 mole) in 15 ml. of phosphorus oxychloride is heated at steam bath temperature for a period of 30 min. Excess phosphorus oxychloride is removed under reduced pressure and dry benzene added. The benzene is evaporated and the treatment repeated two times. Benzene (50 ml.) is added to the residue thus obtained and the insoluble solid collected providing 14.6 g. (70% yield) of N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzamide, m.p. 145°-147° C.
Reaction SMILES: [NH:1]1[C:5]2[NH:6][C:7]([C:9]([O:11]CC)=[O:10])=[CH:8][C:4]=2[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C.O>[NH:1]1[C:5]2[NH:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH:3]=[N:2]1
Reactant: CCOC(=O)c1cc2cn[nH]c2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2cn[nH]c2[nH]1
Temperature: 80 °C
Yield: 20.4 %

Procedure:
Ethyl 1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxylate (1.328 mmol, 0.238 g) was dissolved in ethanol (10 ml). Cesium carbonate (2.66 mmol, 0.866 g) dissolved in water (2 ml) was added and the resulting mixture was stirred at RT for a day after which more cesium carbonate (2.66 mmol, 0.866 g) dissolved in water (2 ml) was added. The temperature was raised to 80° C. for 7 h. Ethanol was evaporated and the residue was diluted with water. pH was adjusted to 4 with 2 M HCl and extracted three times with EtOAc and washed with water. The combined organics were dried, filtered and evaporated. 0.041 g of the title compound was obtained. LC-MS [M+1]: 152.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][C:5]=2[N:6]=1.Br.Cl.[NH2:15][CH2:16][CH2:17][SH:18]>>[NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH2:11][S:18][CH2:17][CH2:16][NH2:15])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: NCCS
Reactant: Nc1nc2ccc(CO)cc2[nH]1
Agent: Br
Agent: Cl
Product: NCCSCc1ccc2nc(N)[nH]c2c1

Procedure:
2-amino-5-hydroxymethylbenzimidazole (2.5 g) prepared according to the method described in Ger. offen. 2,528,846 (1976) and an aqueous 47% hydrobromic acid solution (25 ml) of cysteamine hydrochloride (1.3 g) were subjected to refluxing with heating for five hrs thereby to yield 2-amino-5-[(2-aminoethyl)thiomethyl]benzimidazole.3hydrobromate (melting point: 262°-265° C. (decomposition), 3 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13](Cl)=[O:14].Cl.[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1>>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][NH:17][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:14])=[N:20][CH:21]=1)#[N:24]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: N#Cc1ccc(CN)nc1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1C(=O)NCc1ccc(C#N)cn1
Yield: 93 %

Procedure:
As described for example 1a, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride (0.266 g, 1.2 mmol) was converted, by using 6-aminomethyl-nicotinonitrile hydrochloride salt (0.17 g, 1 mmol) instead of 2-picolylamine, to the title compound (296 mg, 93%) which was obtained as a white solid. MS: m/e: 319.0 [M+H]+.