Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]N(CN(C)C)C.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21]3([CH2:28][C:27](=[O:29])[C:26]4[CH:30]=[C:31]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:32]=[CH:33][C:25]=4[O:24]3)[CH2:20][CH2:19]2)=[CH:12][CH:11]=1)#[N:9].C(O)(=O)C.C(=O)([O-])O.[Na+]>C1COCC1.O>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21]3([C:28](=[CH2:1])[C:27](=[O:29])[C:26]4[CH:30]=[C:31]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:32]=[CH:33][C:25]=4[O:24]3)[CH2:20][CH2:19]2)=[CH:12][CH:11]=1)#[N:9]
Reactant: CN(C)CN(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(C#N)cc3)CC1)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C=C1C(=O)c2cc(NS(C)(=O)=O)ccc2OC12CCN(CCc1ccc(C#N)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
N,N,N',N'-Tetramethyldiaminomethane (1.36 ml, 1.02 g, 10 mmol) was added to a solution of 1'-[2-(4-cyanophenyl)ethyl]-3,4-dihydro-6-methanesulfonamidospiro(2H-1-benzopyran-2,4'-piperidine)-4-one (2.20 g, 5 mmol) and acetic acid (1.14 ml, 1.20 g, 20 mmol) in THF (40 ml) and the mixture was heated under reflux for 24 h. Further N,N,N',N'-tetramethyldiaminomethane (1.36 ml, 1.02 g, 10 mmol) and acetic acid (1.14 ml, 1.20 g, 20 mmol) were added and the mixture was heated under reflux for 6 h, cooled and poured into saturated aqueous sodium hydrogen carbonate (150 ml), diluted with water (50 ml) and extracted with methylene chloride (3×150 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. Toluene (600 ml) was added and the volume was reduced by distillation to 300 ml. Further toluene (300 ml) was added and the volume was reduced by distillation to 300 ml. The mixture was allowed to cool with stirring to room temperature then refrigerated overnight. The solid was collected and dried in vacuo to give the ketone as a yellow solid (1.98 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13](=[O:32])[CH2:14][CH:15]([NH:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(=O)CC(Cc2ccc(N)cc2)NC(=O)[C@@H]2CCCN2)cc(OC)c1OC
Reactant: C=CCOC(=O)Cl
Product: C=CCOC(=O)Nc1ccc(CC(CC(=O)c2cc(OC)c(OC)c(OC)c2)NC(=O)[C@@H]2CCCN2)cc1
Yield: 74.5 %

Procedure:
Following the procedure described in Example 154, treatment of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-aminophenyl)ethylamide (100 mg, 0.23 mmol) with allyl chloroformate (0.036 mL, 0.34 mmol) provided 90 mg of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 2-(4-(N-carboalloxy)aminophenyl)ethylamide as a foam.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)([CH3:6])[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:40][C:41]1[CH:58]=[CH:57][C:44]([CH2:45][C:46]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49](=[O:56])[NH:48][N:47]=2)=[CH:43][C:42]=1[C:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)=[O:60].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)(Cl)Cl.C(OCC)(=O)C.CO>[F:40][C:41]1[CH:58]=[CH:57][C:44]([CH2:45][C:46]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49](=[O:56])[NH:48][N:47]=2)=[CH:43][C:42]=1[C:59]([N:61]1[CH2:66][CH2:65][N:64]([C:3](=[O:5])[C:2]([CH3:1])([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)[CH3:6])[CH2:63][CH2:62]1)=[O:60]
Reactant: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(=O)O
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
To a solution of 2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (0.204 g, 0.81 mmol) in dry DMF (6 mL) was added TBTU (0.289 g, 0.90 mmol) at room temperature under atmosphere of nitrogen. To this 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (0.3 g, 0.81 mmol) and DIPEA (0.303 mL, 1.74 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The progress of reaction was checked by TLC by using mobile phase 5% methanol in chloroform. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4 and solvents were evaporated on a rotatory evaporator under reduced pressure to crude solid which was purified by the flash column chromatography using eluent chloroform:methanol (98.3:1.7) to afford 4-(4-fluoro-3-(4-(2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanoyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one as white solid (0.230 g, 47%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=1)=[O:9].O1[CH2:41][CH2:40]OCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][C:13]([N:7]2[CH2:41][CH2:40][CH2:4][CH2:5][CH2:6]2)=[N:14][CH:15]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(S(C)(=O)=O)nc1-c1ccccc1
Reactant: C1COCCO1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(N2CCCCC2)nc1-c1ccccc1
Reaction time: 16 h
Yield: 191.4 %

Procedure:
To a solution of 0.5 g (0.96 mmol) 2-methylsulfonyl-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml dioxan 0.183 g (2.15 mmol) piperidin was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml H2O. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 20:1) to give 0.48 g (95%) 4-phenyl-2-piperidin-1-yl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a waxy pale yellow solid, MS (ISP): 523.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc2sc3c(c2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O)CCCC3
Temperature: 60 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
To a solution of Methyl (2S)-tert-butoxy[4-(4-chlorophenyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (60 mg, 131 μmol) in tetrahydrofuran (2 mL) and methylated spirit (2 mL) was added an aqueous sodium hydroxide solution (1 M, 790 μL, 790 μmol). The resulting solution was stirred at 60° C. for 3 hours. The volatile solvents were removed in vacuo and the residue diluted with water (10 mL). Dichloromethane (20 mL) was added to the mixture, which was then acidified to pH 5 by the addition of 2 M aqueous hydrochloric acid. The organic layer was separated and washed with water (10 mL) and brine (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was recrystallised from 2-propanol and the resulting solid collected by filtration to give the title compound as a white solid, 11.2 mg, in a 19% yield.
Reaction SMILES: [CH2:1]([N:4]([CH2:11][C:12](OCC)=O)[CH2:5][C:6](OCC)=O)[CH:2]=[CH2:3].[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>>[NH:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:24]=[C:12]1[CH2:11][N:4]([CH2:5][C:6]1[NH:24][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]=1)[CH2:1][CH:2]=[CH2:3]
Reactant: Nc1ccccc1N
Reactant: C=CCN(CC(=O)OCC)CC(=O)OCC
Product: C=CCN(Cc1nc2ccccc2[nH]1)Cc1nc2ccccc2[nH]1
Temperature: 190 °C
Reaction time: 4 h

Procedure:
A mixture of 7.3 g (32.0 mmol) diethyl N-allyliminodiacetate and 6.9 g (64 mmol) o-phenylene diamine was stirred at 190° C. for 4 hour and the formed volatile materials were distilled off. The reaction mixture was then left to cool down to room temperature and acetone (100 ml) was added. The mixture was sonicated for 10 minutes, the formed residue filtered, washed with 2×5 ml acetone and dried under vacuum. Yield—4.5 g (44.0%). 1H NMR (250 MHz, CDCl3□, ppm: 3.22 (d, 2H), 3.95 (m, 4H), 5.20 (m, 2H), 5.90 (m, 1H), 7.15 (m, 4H), 7.53 (m, 4H), 12.11 (br.s 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12](Cl)=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5].[NH3:23]>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12]([NH2:23])=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5]
Reactant: N
Reactant: O=C(Cl)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Solvent: ClCCl
Product: NC(=O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reaction time: 0.25 h

Procedure:
Over a period of 15 minutes, 4.86 g of 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid chloride are added dropwise, while stirring, to 15 ml of a 2.5 % solution of ammonia in dichloromethane. Stirring is carried out for 7 hours at room temperature, small amounts of a finely crystalline precipitate are filtered off and the filtrate is concentrated to dryness by evaporation, chromatographed over silica gel using dichloromethane/methanol (15:1) as eluant and recrystallised from ether/hexane. 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxamide is obtained having a melting point of 174°.
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH2:39]OS(C)(=O)=O)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]23[CH2:39][CH:29]2[C:28](=[O:30])[N:27]([C:31]2[C:32]([CH3:38])=[CH:33][CH:34]=[CH:35][C:36]=2[CH3:37])[CH2:26]3)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C1(COS(C)(=O)=O)CC(=O)N(c2c(C)cccc2C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1CC2(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.4 %

Procedure:
n-BuLi (2.5 M solution in hexanes, 560 μL, 1.39 mmol) was added to a solution of 3,5-bis-trifluoromethylaniline (216.5 μL, 0.545 mmol) in THF (3 mL) at room temperature. The resulting dark brown colored solution was stirred for 10 min at room temperature. A solution of 1-(2,6-dimethyl-phenyl)-3-methanesulfonyloxymethyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step b, 165 mg, 0.465 mmol) in THF (2 mL) was added and stirred for 2 h at 75° C. The reaction mixture was then purified by preparative HPLC (15→85% gradient of MeCN—H2O with 0.1% TFA). The pure fractions were lyophilized to afford 3-(2,6-dimethyl-phenyl)-4-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (22 mg, 10% yield). LC-MS: Rt (retention time): 2.98 min, MS: (ES) m/z 457.2 (M+H+). 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.32 (s, 2H), 7.78 (s, 1H), 7.02-7.18 (m, 3H), 4.18 (d, 1H, J=9.7 Hz), 3.68 (d, 1H, J=9.7 Hz), 2.68-2.75 (m, 1H), 2.18 (s, 3H), 2.08-2.12 (m, 1H), 2.05 (s, 3H), 1.45 (t, 1H, J=3.9 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1>C1CCCCC1.CCOC(C)=O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]#[C:6][CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[N:16]=[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]2=[N:14]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: BrCCCCC#Cc1ccccn1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C(#Cc1ccccn1)CCCCn1nc2ccccc2n1
Yield: 13.3 %

Procedure:
The title compounds were prepared, in accordance with the general method of Example 109(D), from 2-(6-bromo-hex-1-ynyl)-pyridine (250 mg, 1.05 mmol) and benzotriazole (125 mg, 1.05 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 2-(6-(pyridin-2-yl)hex-5-ynyl)-2H-benzo[d][1,2,3]triazole (38 mg, 0.14 mmol, 13%) as a brown oil and (cyclohexane/AcOEt 1:1) to yield 1-(6-(pyridin-2-yl)hex-5-ynyl)-1H-benzo[d][1,2,3]triazole (48 mg, 0.17 mmol, 16%) as a brown oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f18) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[F:37])=[O:28])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH:21]=O)=[O:18])[CH:13]=2)[CH:7]=1.[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42])[CH3:39].C(O)(=O)C.C([BH3-])#N.[Na+].C1COCC1>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[F:37])=[O:28])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][N:46]3[CH2:45][CH2:44][N:43]([C:41]([O:40][CH2:38][CH3:39])=[O:42])[CH2:48][CH2:47]3)=[O:18])[CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCC=O)c[nH]4)c3)cc2F)c1
Reactant: CCOC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(CCNC(=O)c2c[nH]c(-c3cc(Oc4ccc(NC(=O)Nc5cc(C)ccc5F)c(F)c4)ccn3)c2)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(2-oxoethyl)-1H-pyrrole-3-carboxamide (200 mg, 0.40 mmol) and 1-ethoxycarbonylpiperazine (158 mg, 1.0 mmol) in anhydrous DMF (10 ml) was added acetic acid (10 mg, 0.17 mmol). The mixture was stirred under nitrogen for 60 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (1.0 ml, 1.0 mmol). The reaction mixture was stirred for another hour, and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water, and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 5% methanol/chloroform solution to give ethyl 4-(2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)piperazine-1-carboxylate as white solid. Yield: 77 mg, 30%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].Br[C:12]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:13]=1[CH:14]=O>>[Br:20][C:17]1[CH:16]=[C:13]2[C:12](=[CH:19][CH:18]=1)[N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[N:10]=[CH:14]2
Reactant: COc1ccccc1NN
Reactant: O=Cc1cc(Br)ccc1Br
Product: COc1ccccc1-n1ncc2cc(Br)ccc21

Procedure:
In analogy to Example 187, step 1, 2-methoxyphenylhydrazine was reacted with 2,5-dibromobenzaldehyde to give the title compound as a brown oil. MS (m/e)=303.2 [M+H+].
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[SH:16].C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:16][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: Sc1ccc2ccccc2n1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Sc1ccc2ccccc2n1
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
480 mg (1.2 equivalents) of propionyl chloride were added, whilst ice-cooling, to a solution of 1 g of 2-quinolinethiol and 0.83 ml (1.2 equivalents) of triethylamine in 20 ml of anhydrous methylene chloride, and the resulting mixture was stirred for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with ethyl acetate. This mixture was washed twice with a dilute aqueous solution of sodium hydrogencarbonate and was then washed with water. The organic layer was separated and dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by flash chromatography through silica gel, using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the eluent, to give 600 mg of the title compound having an Rf value of 0.4.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[N:30]=[N:29][C:28]([C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:22][N:8]1[C:6]2=[N:7][C:2]([N:34]3[CH:35]=[CH:36][C:31]([C:28]4[N:29]=[N:30][C:25]([C:24]([F:38])([F:23])[F:39])=[CH:26][CH:27]=4)=[CH:32][C:33]3=[O:37])=[CH:3][CH:4]=[C:5]2[C:10]2[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:9]1=2
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nn2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
tert-Butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.11 g, 0.30 mmol), 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (73 mg, 0.30 mmol), and Cs2CO3 (0.11 g, 0.33 mmol) were suspended in DMSO (2.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (13 mg, 0.091 mmol) and copper iodide (75 mg, 0.39 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (70 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (30 mL), and washed with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (2×30 mL). Activated charcoal was added to the organic solution, and the resulting suspension was filtered through a Celite® plug and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 4 column volumes) gave the title compound (70 mg, 43%) as a yellow powder: 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=9.0 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.41 (d, J=1.5 Hz, 1H), 7.22 (dd, J=7.5, 1.5 Hz, 1H), 4.60 (s, 2H), 3.77 (t, J=5.5 Hz, 2H), 3.71 (s, 3H), 2.90 (t, J=5.5 Hz, 2H), 1.45 (s, 9H); ESI MS m/z 527 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19].N12CCN(CC1)CC2.O>O1CCCC1.CCCCCCC>[CH3:13][C:11]([CH3:12])([CH3:14])[CH2:10][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:18](=[O:19])[N:17]([CH3:16])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:7][CH:6]=1)=[O:15]
Reactant: CC(C)(C)CC(=O)Nc1ccc(O)nc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)C)cn1)c1ccccc1
Yield: 79.1 %

Procedure:
A solution of N-(6-hydroxy-pyridin-3-yl)-3,3-dimethyl-butyramide (0.42 g, 2.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.37 g, 2.20 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.25 g, 2.20 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for 2.5 hours. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was redissolved in ethyl acetate and the solution was filtered over a short pad of silicagel. Evaporation of the solvent and crystallisation of the solid from ethyl acetate:heptane yielded the title compound (0.54 g, 79% yield) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH2:18][C:19]2[N:23]([CH3:24])[N:22]=[CH:21][N:20]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[C:11]1[CH:15]=[C:14]([CH3:16])[O:13][N:12]=1.C([Sn](CCCC)(CCCC)[C:30]1[O:31][CH:32]=[CH:33][CH:34]=1)CCC.[SnH4]>O1CCOCC1.[Pd]>[O:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:2]1[C:3]([O:17][CH2:18][C:19]2[N:23]([CH3:24])[N:22]=[CH:21][N:20]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[C:11]1[CH:15]=[C:14]([CH3:16])[O:13][N:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Cc1cc(-c2nncc3c(Br)c(OCc4ncnn4C)nn23)no1
Agent: [Pd]
Agent: [SnH4]
Solvent: C1COCCO1
Product: Cc1cc(-c2nncc3c(-c4ccco4)c(OCc4ncnn4C)nn23)no1
Yield: 196.9 %

Procedure:
A stirred mixture of 3-bromo-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-[1,2,4]triazol-5-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (Example 7) (80 mg, 0.20 mmol) in dioxan (10 mL) containing 2-tri-n-butylstannylfuran (146 mg, 0.41 mmol) was degassed with nitrogen for 20 min. Tetrakis-triphenylphosphine palladium(0) (50 mg) and copper(I)iodide (5 mg) were added and the mixture heated at reflux for 8 h. Further stannane (146 mg, 0.41 mmol) and palladium catalyst (50 mg) were added and the mixture heated at reflux for 16 h. The solvent was evaporated and the residue purified on silica eluting with 5% MeOH/DCM to give a yellow solid (149 mg). The yellow solid was re-chromatographed on silica eluting with 5% MeOH/DCM to give a yellow solid (29 mg) which was triturated with diethylether to give the title compound (15 mg, 19%) as a yellow solid. mp 226-228° C. 1H NMR (360 MHz, CDCl3) δ1.58 (9H, s), 2.61 (3H, s), 4.10 (3H, s), 5.78 (2H, s), 6.52-6.56 (1H, m), 6.75-6.79 (1H, m), 6.96 (1H, s), 7.57 (1H, s), 7.91 (1H, s), 9.71 (1H, s). Found: C, 52.68; h, 3.47; N, 28.64; C17H14N8O3.0.05(CH2Cl2).0.25(H2O) requires: C, 52.90; H, 28.95%.