Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][C:32]([C:36]3[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=3)=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:42])=[CH:20][N:19]=1>>[Cl:42][C:21]1[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][C:32]([C:36]3[CH:37]=[N:38][N:39]([CH3:41])[CH:40]=3)=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide in an analogous manner to Example 308c. Product isolated as a white foam (81 mg, 40%). LCMS (m/e) 579; 1H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 8.07 (s, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.43 (s, 1H), 7.37 (d, 1H, J=10.9 Hz), 7.23 (s, 1H), 7.06 (d, 1H, J=8.1 Hz), 6.93-6.83 (m, 2H), 6.22-6.13 (m, 1H), 4.00 (s, 3H), 3.50 (t, 2H, J=5.5 Hz), 3.37 (s, 3H), 2.92 (d, 3H, J=4.8 Hz), 2.88-2.80 (m, 2H), 2.79-2.71 (m, 2H), 2.71-2.63 (m, 4H), 2.63-2.54 (m, 2H); 19F-NMR (CDCl3, 400 MHz) δ −113.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]4[O:10][C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[CH:8][C:6]=4[N:7]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: Clc1nc(N2CCOCC2)c2oc(-c3ccccc3)cc2n1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3o2)cc1
Temperature: 150 °C
Reaction time: 0.42 h

Procedure:
2-Chloro-4-morpholino-6-phenylfuro[3,2-d]pyrimidine 44 (50 mg, 1.0 eq) was dissolved in toluene/ethanol/water (4:2:1, 2.8 ml) and treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (97 mg, 2.5 eq), PdCl2(PPh3)2 (13.3 mg, 0.12 eq) and sodium carbonate (59 mg, 3.5 eq). The vial was sealed and heated with stirring in the microwave to 150° C. for 25 minutes. The crude reaction mixture was concentrated and purified by reverse phase HPLC to afford 201 MS (Q1) 398 (M)+.
Reaction SMILES: [P:1]([O-:40])([O:36][CH2:37][CH2:38]Br)([O:3][CH2:4][CH:5]([O:24][C:25]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][N:26]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2].[S:41]1[CH:45]=[CH:44][N:43]=[CH:42]1>C1(C)C=CC=CC=1>[P:1]([O-:40])([O:36][CH2:37][CH2:38][C:42]1[S:41][CH:45]=[CH:44][NH+:43]=1)([O:3][CH2:4][CH:5]([O:24][C:25]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][N:26]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: c1cscn1
Reactant: CCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCBr)Oc1cc(-c2ccccc2)on1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCc1[nH+]ccs1)Oc1cc(-c2ccccc2)on1
Reaction time: 120 h

Procedure:
A mixture of 0.925 g of the crude (2RS)-3-hexadecyloxy-2-(5-phenyl-3-isoxazolyloxy)propyl 2-bromoethyl phosphate obtained as described in the first part of Example 7 and 0.51 ml of thiazole in 0.8 ml of toluene was heated on an oil bath kept at 70° C. for 5 days, whilst stirring. The mixture was then cooled and freed from toluene by evaporation under reduced pressure. 15 ml of chloroform were then added to the residue, followed by 0.296 g of silver carbonate. The mixture was then heated under reflux for 1 hour. At the end of this time, the mixture was cooled, an insoluble material was filtered off and the solvent was stripped off from the filtrate by evaporation under reduced pressure. The residue was subjected to column chromatography through 20 g of silica gel. 0.117 g of the title compound was obtained as a viscous oil from the fractions eluted with a 1:1 by volume mixture of methanol and methylene chloride and with a 35:60:5 by volume mixture of methanol, methylene chloride and water.
Reaction SMILES: C[N:2]([CH3:8])/[CH:3]=[CH:4]/[C:5](=O)[CH3:6].[NH:9]([C:11]1[CH:16]=[CH:15][CH:14]=CN=1)[NH2:10]>C(O)C>[CH3:14][C:15]1[CH:16]=[CH:11][N:9]([C:8]2[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=2)[N:10]=1
Reactant: CC(=O)/C=C/N(C)C
Reactant: NNc1ccccn1
Solvent: CCO
Product: Cc1ccn(-c2ccccn2)n1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
(3E)-4-(dimethylamino)but-3-en-2-one (255 mg, 2.25 mmol) and 2-hydrazinopyridine (369 mg, 3.38 mmol) were added to ethanol (3 ml). The reaction mixture was heated to 150° C. in the Biotage Initiator Series microwave reactor. After 30 minutes, the reaction mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel, (ethyl acetate/isohexane gradient) to afford 2-(3-methyl-1H-pyrazol-1-yl)pyridine (faster eluting isomer) and 2-(5-methyl-1H-pyrazol-1-yl)pyridine (slower eluting isomer).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(Cl)(Cl)Cl.C(=O)=O.[Si:14]([O:31][C:32]1[CH:49]=[CH:48][C:47]2[C@@H:46]3[C@H:37]([C@H:38]4[C@@:42]([CH2:44][CH:45]3[OH:50])([CH3:43])[CH:41]3[O:51][CH2:52][CH2:53][O:54][CH:40]3[CH2:39]4)[CH2:36][CH2:35][C:34]=2[CH:33]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[Si:14]([O:31][C:32]1[CH:49]=[CH:48][C:47]2[C@@H:46]3[C@H:37]([C@H:38]4[C@@:42]([CH2:44][C:45]3=[O:50])([CH3:43])[CH:41]3[O:51][CH2:52][CH2:53][O:54][CH:40]3[CH2:39]4)[CH2:36][CH2:35][C:34]=2[CH:33]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](Oc1ccc2c(c1)CC[C@@H]1[C@@H]2C(O)C[C@]2(C)C3OCCOC3C[C@@H]12)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](Oc1ccc2c(c1)CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C3OCCOC3C[C@@H]12)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 83.8 %

Procedure:
To a stirred solution of 1.5 mL (16.5 mmol) of oxalyl chloride in 15 mL of freshly distilled dichloromethane was added dropwise 2.35 mL (33.0 mmol) of dimethyl sufoxide at −65° C. (chloroform/dry ice bath) under argon atmosphere. After 10 minutes, a solution of 6.2 gm (10.9 mmol) of 3-tert-butyldiphenylsilyloxy-17-ethylenedioxyestra-1,3,5(10)-11-ol 38 in 15 mL of dichloromethane was added dropwise, and the reaction mixture was stirred for 40 minutes at the same temperature. Then, a 12 mL (87.3 mmol) of triethylamine was added at −65° C., slowly allowed to attain room temperature, washed with saturated NH4Cl solution, water, brine, and dried (Na2SO4). Evaporation of the solvent furnished a gum, which was chromatographed (15% ethyl acetate/hexanes) to afford 5.18 g (84%) the product 39.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][CH:5]([N:7]([CH2:9][C@@H:10]2[C@H:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH2:29])[O:11]2)[CH3:8])[CH2:4]1.[C:30]([C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[NH2:29][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[C:26]=1[N:27]=[CH:28][N:20]2[C@H:12]1[C@@H:13]2[O:17][C:16]([CH3:19])([CH3:18])[O:15][C@@H:14]2[C@@H:10]([CH2:9][N:7]([CH3:8])[CH:5]2[CH2:4][CH:3]([CH2:2][NH:1][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=3)=[O:42])[CH2:6]2)[O:11]1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CN)C1
Solvent: ClCCl
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CNC(=O)Nc2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 9-((3aR,4R,6R,6aR)-6-(((3-(aminomethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine in DCM (4 ml) was added 1-tert-butyl-4-isocyanatobenzene (37 mg). The mixture was stirred at RT for 1 h. The mixture was concentrated and purified via preparative-TLC (DCM:MeOH=10:1) to give the title compound (55 mg, Yield 45% for two steps). ESI-MS (m/z): 578.3[M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=2I)=[O:19])[CH2:14][CH2:13]1.[CH3:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=2[N:34]2[CH:33]=[C:32]([CH3:31])[CH:36]=[N:35]2)=[O:19])[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3F)CC2)c1
Reactant: Cc1cn[nH]c1
Product: Cc1cnn(-c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(C(F)(F)F)cc3F)CC2)c1
Yield: 30 %

Procedure:
The title compound was prepared according to the procedure described for example 294 from [4-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-iodo-5-methanesulfonyl-phenyl)-methanone (compound CN) and 4-Methyl-1H-pyrazole (30% yield, light brown solid, MS (m/e): 511.2 (M+H, 100%)
Reaction SMILES: [F:1][C:2]1[C:14]([N:15]=[C:16]=[O:17])=[CH:13][C:5]2[N:6]([CH2:10][CH:11]=[CH2:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N:18]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1.C1(C)C=CC=CC=1.C(N(CC)CC)C>O>[F:1][C:2]1[C:14]([NH:15][C:16]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][N:18]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:17])=[CH:13][C:5]2[N:6]([CH2:10][CH:11]=[CH2:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCCCN1
Reactant: C=CCn1c(=O)sc2cc(F)c(N=C=O)cc21
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCn1c(=O)sc2cc(F)c(NC(=O)N3CCCCN3C(=O)OCC)cc21
Yield: 69.6 %

Procedure:
6-Fluoro-3-(2-propenyl)-2(3H)-benzothiazolon-5-yl isocyanate (1.99 g) and ethyl hexahydropyridazine-1-carboxylate (1.26 g) were added to toluene (8 ml). A catalytic amount of triethylamine was added thereto, and the resultant mixture was stirred at 25° C. for 12 hours. Water was added thereto, and the resultant mixture was extracted with toluene. The extract was washed with water, dried and concentrated to give ethyl 2-[6-fluoro-3-(2-propenyl)-2(3H)-benzothiazolon-5-ylaminocarbonyl]-hexahydropyridazine-1-carboxylate (2.26 g). m.p., 161.2° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]2[C:13]([NH2:19])=[CH:14][CH:15]=[C:16](C)[CH:17]=2)[N:4]=1.[N:20]#[C:21]Br.O.[CH2:24](O)C>>[NH2:20][C:21]1[N:11]([C:5]2[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=2)[C:12]2[CH:17]=[CH:16][C:15]([CH3:24])=[CH:14][C:13]=2[N:19]=1
Reactant: CCO
Reactant: COc1cc(OC)nc(Nc2cc(C)ccc2N)n1
Reactant: N#CBr
Solvent: O
Product: COc1cc(OC)nc(-n2c(N)nc3cc(C)ccc32)n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
N′-(4,6-dimethoxypyrimidin-2-yl)-4-methylbenzene-1,2-diamine (2.00 g) was dissolved in ethanol, and cyanogen bromide (1.00 g) was added thereto at room temperature, followed by stirring at 60° C. for 1 hour. Water was added, and the crystals were collected by filtration, washed with water and dried to obtain 2.03 g of the desired product as a white powder (m.p. at least 300° C.).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[N:16]=[CH:15][S:14][C:12]3=2)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(O)C>O>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[N:16]=[CH:15][S:14][C:12]3=2)[NH:7]1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Nc1ccc(S(=O)(=O)NCc2ccncc2)cc1
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)NCc2ccncc2)cc1
Yield: 74.6 %

Procedure:
To a 250-ml round bottom flask was added a magnetic stir bar, 8-[ethoxymethylidene]-6H-[1,3]thiazolo[5,4-e]indol-7-one (1.98 grams, 8.05 mmol), 4-amino-N-(4-pyridinylmethyl)benzenesulfonamide (2.16 grams, 8.2 mmol) and 95% ethanol (80 ml). The round bottom reaction flask was fitted with a water cooled reflux condenser. The reaction vessel was placed in an oil bath at room temperature with stirring and the temperature of the oil bath was then raised to a gentle reflux and maintained at that temperature for approximately 36 hours. The reaction vessel was removed from the oil bath and the hot mixture was filtered with the solids being collected by suction filtration. The resultant solid was washed with excess 95% ethanol and collected by suction filtration. The solid was then dried under vacuum for two days at room temperature to yield 2.785 grams (74.7%) of the thiazolindolinone compound. MS (M+H)=464.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[N:14][CH:13]=[CH:12]3)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][N:28]=1>N1C=CC=CC=1>[ClH:26].[N:28]1[CH:27]=[CH:32][CH:31]=[N:30][C:29]=1[N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[N:14][CH:13]=[CH:12]3)[CH2:4][CH2:3]1
Reactant: Clc1ccncn1
Reactant: c1cc2cc(OC3CCNCC3)ccc2cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: c1cnc(N2CCC(Oc3ccc4cnccc4c3)CC2)nc1
Temperature: 65 °C
Reaction time: 6 h

Procedure:
150 mg of 6-(Piperidine-4-yloxy)-isoquinoline hydrochloride (124) are dissolved in 10 mL of dry pyridine. 177 mg of triethylamine and 69 mg of 4-chloropyrimidine are added and the solution is stirred at 65° C. for 6 hours. The reaction mixture is poured on brine and extracted three times with ethyl acetate. The combined organic layers are dried over magnesium sulfate, evaporated to dryness and the crude product is purified by preparative HPLC. The product is converted into the corresponding HCl salt by taking up the product in 20 mL of 1 N hydrochloric acid followed by lyophilization. Yield: 47 mg. Rt=1.05 min (Method #2). Detected mass: 307.1 (M+H+).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f16) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>>[CH3:23][O:24][CH2:25][CH2:26][N:27]([CH3:28])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: CNCCOC
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: COCCN(C)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 2-methoxy-N-methylethanamine(1.2 equiv) to give 182 (15.1 mg, M+1 385.1)
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[I:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19]([CH3:20])=[CH:18][C:17](=[O:21])[C:16]([C:22]([OH:24])=[O:23])=[N:15]2)=[CH:10][CH:9]=1.O>C(Cl)(Cl)Cl>[I:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19]([CH3:20])=[CH:18][C:17](=[O:21])[C:16]([C:22]([O:24][CH3:1])=[O:23])=[N:15]2)=[CH:10][CH:9]=1
Reactant: CO
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(I)cc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1nn(-c2ccc(I)cc2)c(C)cc1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
To 50 ml of methanol, cooled to -5°, there is added dropwise 2.62 g (0.022 mol) of thionyl chloride (pot temperature maintained between -5° C. and 0° C.). The solution is stirred at 0° C. for 15 min and to it there is added 7.12 g (0.02 mol) of 1-(4-iodophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid. (See Example 3). The suspension formed is stirred at room temperature for 3 days and to it there is added 200 ml of water. The suspension that forms is stirred at room temperature for 2 days and is vacuum filtered. The filter cake is air dried to afford 4 g of crude product. The crude product is suspended in 25 ml of chloroform and filtered. The filtrate is concentrated in vacuo to afford 3.5 g (47% yield) of product, mp 185°-187° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[C:28]([C:35]([F:38])([F:37])[F:36])[CH:27]=1.Cl>C(Cl)Cl>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:2][CH:3]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:31])=[C:28]([C:35]([F:36])([F:37])[F:38])[CH:27]=1
Reactant: CCOC(=O)C(N)C(=O)c1ccccc1C
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
6.2 g (0.024 mol) of ethyl 2-amino-3-oxo-3-o-tolylpropionate hydrochloride were dissolved in methylene chloride, and 9.7 g (0.096 mol) of triethylamine were added. At 0° C., 5.4 g (0.024 mol) of 4-fluoro-2-trifluoromethylbenzoyl chloride, dissolved in methylene chloride, were added dropwise. The mixture was stirred at room temperature (RT) for 1 h, and 5% strength hydrochloric acid was then added. The organic phase was separated off, washed and dried, and the solvent was removed. Chromatographic purification (silica gel column, cyclohexane/ethyl acetate) gave 4.7 g of the title compound as colorless crystals.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])[NH2:3].[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18].[CH2:22](O)[CH3:23]>>[CH2:22]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N:2]2[C:17]([NH2:18])=[CH:16][C:15]([C:14]([CH3:21])([CH3:20])[CH3:13])=[N:3]2)[CH:5]=1)[CH3:23].[NH2:18][C:17]1[N:2]([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[C:7]([OH:9])=[O:8])[N:3]=[C:15]([C:14]([CH3:21])([CH3:20])[CH3:13])[CH:16]=1
Reactant: NNc1cccc(C(=O)O)c1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CCO
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2cccc(C(=O)O)c2)n1
Product: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2N)c1
Yield: 36 %
Yield: 40 %

Procedure:
A mixture of 3-hydrazino-benzoic acid hydrochloride (200 g, 1.06 mol) and 4,4-dimethyl-3-oxo-pentanenitrile (146 g, 1.167 mol) in ethanol (2 L) was heated to reflux overnight. The reaction solution was evaporated under reduced pressure. The residue was purified by column chromatography to give 3-(5-amino-3-t-butyl-pyrazol-1-yl)-benzoic acid ethyl ester (116 g, 40%) as a white solid together with 3-(5-amino-3-t-butyl-pyrazol-1-yl)-benzoic acid (93 g, 36%). 3-(5-amino-3-t-butyl-pyrazol-1-yl)-benzoic acid and ethyl ester: 1H NMR (DMSO-d6): 8.09 (s, 1H), 8.05 (brd, J=8.0 Hz, 1H), 7.87 (br d, J=8.0 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 5.64 (s, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H), 1.28 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:23][CH2:24][CH2:25][OH:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.O>[CH2:16]([N:23]([CH2:24][CH2:25][OH:26])[C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: OCCNCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (2.0 g, 9.20 mmol) in CH2Cl2 (40 mL) were added 2-(benzylamino)ethanol (1.3 g, 8.80 mmol), HATU (5.30 g, 13.8 mmol) and Et3N (2.80 g, 27.6 mmol) under N2. The mixture was stirred at rt overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography on silica gel to afford (R)-tert-butyl (1-(benzyl(2-hydroxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (2.80 g, 88% yield) as a white solid. LC-MS m/z 351.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[H-].[Na+].[CH2:19](Br)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>CN(C)C=O>[CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[N:6]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2N(CC(=O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
In an argon gas stream, 2.0 g of 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H-1,4-benzoxazine was added gradually to 0.4 g of 60% sodium hydride in oil in 40 ml of dry N,N-dimethylformamide. The mixture was stirred at room temperature for 1 hour and 2.68 g of phenacyl bromide was added. The mixture was stirred at room temperature for 1 hour, after which the solvent was distilled off under reduced pressure. The residue was diluted with 50 ml of water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column and elution was carried out with methylene chloride-ethyl acetate. Recrystallization from ethyl acetate-ether gave 2.04 g of 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-4-phenacyl-2H-1,4-benzoxazine.