Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[Mg].Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2C=C[C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]C)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.II.C(N1CCCCC1)=O.Cl.[CH2:36]1[CH2:40][O:39][CH2:38][CH2:37]1>O>[CH2:16]([C:15]1[CH:40]=[CH:36][C:37]([CH:38]=[O:39])=[C:13]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][CH:5]=[CH:10][CH:9]=2)[CH:14]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCc1ccc(C#Cc2ccc(Br)cc2)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: II
Agent: N#N
Solvent: O
Product: CCCCCCc1ccc(C=O)c(C#Cc2ccccc2)c1
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
To a dry 2 L three-necked flask under a flow of N2 containing magnesium turnings (13.579 g; 558.69 mmol) in dry THF (165 mL) at reflux (temperature of bath oil of 85° C.), an activating, small amount of 1-bromo-4-[(4-hexylphenyl) ethynyl] benzene (VIIb) (10.400 g; 30.474 mmol) was added in one portion. N2 flow and stirring were stopped. Reaction mixture was heated at reflux for 5 minutes, then several iodine crystals were added keeping vigorous reflux to start the reaction. The reaction mixture went colorless after 5 minutes and reaction mixture turned black-green after an additional minute. A solution of the remaining amount of 1-bromo-4-[(4-hexylphenyl) ethynyl] benzene (VIIb) (162.94 g; 477.42 mmol) in dry THF (360 mL) was added drop wise over 40 minutes into the reaction mixture while keeping gentle reflux. Reflux was maintained for 20 minutes then temperature was allowed to cool to room temperature under stirring for 2 h30. The reaction mixture was cooled to 3° C. and a solution of dry 1-formyl-piperidine (84.60 mL; 761.85 mmol) in dry THF (360 mL) was added drop wise over 1 hour maintaining temperature at 5° C. (maximum temperature: 7.3° C.). The reaction mixture was then allowed to warn to room temperature and it was stirred overnight. The reaction mixture was cooled to 18° C. and 3N HCl (300 mL) was added until the solution was acidic (pH=1). Water was added (500 mL) and extraction was performed with MTBE (500 mL×3). Organic phase was washed successively with water (500 mL×2), saturated solution of NaHCO3 (500 mL×1) and brine (500 mL×1). It was then dried over MgSO4, filtered and concentrated to give an orange solid. It was taken up in Pet ether (400 mL) and left at 4° C. After 16 h the suspension was filtered and washed with Pet ether (2×300 mL) to give after drying under vacuum the first crop m=105.76 g. Filtrate was concentrated and taken up in Pet ether (100 mL). The resulting solid was washed with Pet ether (2×100 mL), and dried to give the second crop m=6.0 g. The title compound was obtained as a white solid (m=111.76 g) in a 76% yield. Melting point: 80° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](Br)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]1[NH:27][CH2:26][CH2:25][NH:24][CH2:23]1>CN1CCCC1=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([N:24]4[CH2:25][CH2:26][NH:27][CH:22]([CH3:21])[CH2:23]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)c(Br)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC1CNCCN1
Solvent: CN1CCCC1=O
Product: Cc1c(F)c(N2CCNC(C)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 90 °C
Yield: 50.6 %

Procedure:
To a solution of 1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.58 g) in N-methyl-2-pyrrolidone (5 ml) is added 3-methylpiperazine (0.65 g), and the mixture is heated at 90° C. for 20 minutes. After the solvent is distilled off under reduced pressure, ethanol is added to the residue, and the crystals are separated by filtration and are recrystallized from ethyl acetate-ethanol to give 1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (310 mg), as white powdery crystals, m.p. 206°-208° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:34])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=4)[CH:22]=3)[CH2:18][C:17](=[O:34])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (4-chloro-5-methyl-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M66) (0.46 g, 0.93 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (270 mg, 77%).
Reaction SMILES: [CH2:1]([Si:11]([Cl:14])([Cl:13])Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[Cl:14][Si:11]([Cl:13])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCC[Si](Cl)(Cl)Cl
Reactant: CCCCCCCCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCCCCCCC[Si](Cl)(Cl)CCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Tetrahydrofuran (82 mL) and n-decyltrichlorosilane (Tokyo Chemical Industry Co., Ltd., 14.5 g, 52.6 mmol) were placed in a 500 mL four-necked flask in a nitrogen atmosphere, and cooled to 0° C. n-decyl magnesium bromide (Sigma-Aldrich Co. LLC., 1.0 M, 58 ml) was added dropwise, and the mixture was agitated for 1 hour at 10° C. or less. The temperature was raised gradually to room temperature over the course of about 1 hour, and the mixture was left standing overnight. The precipitated salt was filtered out, the tetrahydrofuran was removed by concentration under reduced pressure, and distillation under reduced pressure was performed to obtain the target dichlorodi-n-decylsilane (Compound E21) (150° C./0.1-0.2 Torr, 13.1 g, yield 65%).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[C:3]#[C:4][C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1>C1C(Cl)=CC=C(Cl)C=1>[CH3:1][C:2]1([CH3:20])[CH:3]=[C:4]([C:5]2[N:6]=[CH:7][CH:8]=[CH:9][N:10]=2)[C:19]2[CH:18]=[C:15]([C:16]#[N:17])[CH:14]=[CH:13][C:12]=2[O:11]1
Reactant: CC(C)(C#Cc1ncccn1)Oc1ccc(C#N)cc1
Solvent: Clc1ccc(Cl)cc1
Product: CC1(C)C=C(c2ncccn2)c2cc(C#N)ccc2O1
Yield: 62.2 %

Procedure:
580 mg of 4-[1,1-dimethyl-3-(2-pyrimidinyl)-2-pro pynyloxy]benzonitrile were heated at reflux for 3 hours in 20 ml of dichlorobenzene. The solution was allowed to cool and was then evaporated to dryness. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) and subsequently ethyl acetate/petroleum ether (1:1) for the elution. There was obtained 361 mg of 2,2-dimethyl-4-(2-pyrimidinyl)-2H-1-benzopyran-6-carbonitrile which melted at 108°-109.5° C. after recrystallization from tert-butyl methyl ether.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[I-].[Na+].[Br:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:10].[CH2:19]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Br.C(O)C>O1CCCC1>[BrH:7].[CH2:19]([N:26]1[CH2:31][CH2:30][C:29]([CH2:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)([OH:32])[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(=O)CC2(O)CCN(Cc3ccccc3)CC2)cc1
Reaction time: 2 h
Yield: 36.3 %

Procedure:
Anhydrous cerium chloride (0.99 g, 4.0 mmol) and sodium iodide (1.8 g, 12.0 mmol) are added to 10 ml of anhydrous tetrahydrofuran as a solvent to form a suspension. Dissolving 0.92 g (4.0 mmol) of 2-bromo-1-(4-methoxyphenyl)-ethanone and 0.76 g (4.0 mmol) of N-benzyl-4-piperidone in 10 ml of anhydrous tetrahydrofuran, and the solution is added dropwise to the above suspension and reacting at room temperature for 2 hours. Operating according to the post-treatment procedure in General Method three, and a salt is formed by acidifying with hydrobromic acid/ethanol solution, which is recrystallized in ethyl acetate/ethanol to obtain 0.61 g of a white crystal, with yield of 34.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][S:15]([C:18]3[CH:48]=[CH:47][C:21]([CH2:22][CH2:23][NH:24][CH2:25][C@H:26]([OH:46])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][Si](C(C)C)(C(C)C)C(C)C)=[CH:31][CH:30]=4)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[N:10]=2)=[CH:5][CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Cl-].[NH4+]>[OH:46][C@@H:26]([CH2:25][NH:24][CH2:23][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([S:15]([CH2:14][C:11]2[N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[O:13][N:12]=2)(=[O:17])=[O:16])=[CH:48][CH:47]=1)[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1
Reactant: COc1ccc(-c2nc(CS(=O)(=O)c3ccc(CCNC[C@H](O)COc4ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc4)cc3)no2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(CS(=O)(=O)c3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)no2)cc1
Reaction time: 6 h
Yield: 60.7 %

Procedure:
To a solution of the amino alcohol of Example 28(0.57 g, 0.733 mmol) in THF (11 mL) was added a 1M solution of TBAF (0.15 mL, 0.15 mmol). The reaction mixture was stirred for 6 h. TLC shows the absence of starting material, so 3 drops of a saturated aqueous ammonium chloride solution was added. The reaction mixture was evaporated in vacuo to dryness and the residue was flash chromatographed (silica gel; dichloromethane/chloroform/methanol: 6/3/1) to afford 0.240 g of the title compound as a white foam.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:34][C@@H:35]1[CH:40]2[CH2:41][CH2:42][N:37]([CH2:38][CH2:39]2)[CH2:36]1.CO>C(Cl)Cl>[N:37]12[CH2:42][CH2:41][CH:40]([CH2:39][CH2:38]1)[C@@H:35]([NH:34][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=1)[CH2:36]2
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
TEA (50 μL, 0.35 mmol) is added to a suspension of 4-phenoxybenzoic acid (75 mg, 0.35 mmol) in CH2Cl2 (1 mL). Diphenylchlorophosphate (62 μL, 0.3 mmol) is added and the resulting solution is stirred at room temperature for 30 minutes. A solution of (R)-3-aminoquinuclidine (1M in DMF, 0.2 mL, 0.2 mmol) is added and the resulting solution is stirred overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50W×2 ion exchange resin (H+ form). The resin is washed with MeOH and then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness to yield the desired product (49 mg, 76%). MS for C20H22N2O2 (ESI) (M+H)+ m/z 323.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.[NH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[OH:22].CCN(C(C)C)C(C)C>C(O)C>[OH:22][C@H:18]1[CH2:19][CH2:20][CH2:21][C@@H:17]1[NH:16][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: N[C@H]1CCC[C@@H]1O
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1N[C@H]1CCC[C@@H]1O
Temperature: 60 °C
Yield: 72.8 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.4 g, 6.0 mmol), (1S,2S)-2-aminocyclopentanol hydrochloride (0.7 g, 6.9 mmol) and DIEA (1.0 g) in ethanol (20 mL) was heated at 60° C. for 15 h. After being cooled to room temperature, the reaction solution was concentrated and the residue was purified on silica gel column (eluting with 0-10% ethyl acetate in petroleum ether) to give ethyl 4-((1S,2S)-2-hydroxycyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate (1.3 g, 4.37 mmol, yield 73%) as a white solid. MS (ESI): m/z 298.5 [M+1]+.
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[C:18]([C:20]([NH:22][C:23]3[C:32]([CH3:33])=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][C:24]=3[CH3:34])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:6][CH2:5]1.CO>C1COCC1>[OH:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:19]=[C:18]([C:20]([NH:22][C:23]3[C:24]([CH3:34])=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][C:32]=3[CH3:33])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:8][CH2:9]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(O)CC3)nc3ccccc23)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc(C)c1NC(=O)c1cc(N2CCC(O)CC2)nc2ccccc12
Reaction time: 5 h
Yield: 39.7 %

Procedure:
A solution of aqueous 2N NaOH (2.00 ml) is added to a stirred solution of methyl 4-(2-(4-hydroxypiperidin-1-yl)quinoline-4-carboxamido)-3,5-dimethylbenzoate (0.13 g, 0.0003 mol) in THF:MeOH (5 ml:2 ml). After 5 h at 50° C., the organic solvent is removed under reduced pressure and the residue is diluted with water acidified to pH 6 with aqueous 1N HCl and extracted with ethyl acetate (2×20 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with pentane and diethyl ether and filtered to afford the title compound as a light yellow solid (0.05 g, 40%). Mass spectrum (m/z): 420.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15]([O:17]CC)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:22]([NH2:24])[CH3:23]>>[CH2:22]([NH:24][C:15](=[O:17])[CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:21][CH2:20][C:5]1=2)[CH3:23]
Reactant: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: CCN
Product: CCNC(=O)Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetate (100 mg) and ethylamine (1 ml) was heated at 120° C. for 15 h to obtain N-ethyl-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide (CD23) after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.CON(C)[C:18](=[O:22])[CH2:19][O:20][CH3:21]>CCOCC>[Cl:9][C:4]1[CH:3]=[C:2]([C:18](=[O:22])[CH2:19][O:20][CH3:21])[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: COCC(=O)N(C)OC
Reactant: Clc1ccc(Br)cc1Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COCC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 4-bromo-1,2-dichlorobenzene (2.04 g, 9.01 mmol) and ether (5 mL) cooled to −78° C. was added as a steady stream n-BuLi (3.61 ml, 9.01 mmol) and the reaction was stirred for 10 min then cannulated into a solution of N,2-dimethoxy-N-methylacetamide (1.0 g, 7.51 mmol) and ether (10 mL) which was stirred for an additional 20 min. The reaction was quenched with water and extracted with EtOAc. The organic fractions were dried, filtered and concentrated. The crude product which was purified by SiO2 chromatography eluting with hexane/EtOAc (9:1) to afford 1.30 g (79.0%) of 1-(3,4-dichlorophenyl)-2-methoxyethanone as a white solid (192).
Reaction SMILES: Br[CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1.[C:16]1([NH:22][CH2:23][CH2:24][NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3][CH:2]([NH:25][CH2:24][CH2:23][NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:8]=1)#[N:13]
Reactant: NCCNc1ccccc1
Reactant: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(NCCNc2ccccc2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 409.3 %

Procedure:
A solution of 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (0.75 g, 2.82 mmole, from Example 8,part B) and N-phenylethylenediamine (8.84 g, 10 eq.) containing NaHCO3 (2.40 g, 5 eq.) in N,N-dimethylformamide (15 ml) was stirred for 48 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and distilled H2O. The organic phase was washed with distilled H2O, saturated NaCl solution, dried over Na2SO4 and evaporated in vacuo to obtain 3.71 g of an orange gum. The crude product was chromatographed on silica eluting with 3:2 hexane/ethyl acetate to obtain 0.36 g (40%) of the title compound as a colorless gum which solidified upon standing. 1H NMR (CDCl3) δ7.91 (s, 1H), 7.38 (dd, J=2.34 and 8.79 Hz, 1H), 7.19 (m, 2H), 6.79 (d, J=8.21 Hz, 1H), 6.70 (m, 3H), 3.87 (dd, J=5.86 and 11.14 Hz, 1H), 3.26 (m, 2H), 3.10 (m, 1H), 2.86 (m, 1H), 2.20 (dd, J=5.87 and 12.90 Hz, 1H), 1.58 (d, J=12.30 Hz, 1H), 1.45 (s, 3H), 1.27 (s, 3H); 13C NMR (CDCl3) δ157.63, 148.16, 132.40, 132.09, 129.21, 125.32, 119.56, 118.09, 117.52, 112.97, 102.89, 76.83, 49.24, 44.89, 44.00, 39.25, 29.69, 24.96; MS: (M+H)+ @322.
Reaction SMILES: [CH3:1][N:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([NH2:5])=O.C(N(CC)CC)C.O>C(Cl)(Cl)Cl.[OH-].[Na+]>[CH3:1][N:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]#[N:5]
Reactant: CN(Cc1ccccc1)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C#N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.1 %

Procedure:
To N-methyl-N-benzylurea (1.64 g, 0.01 mol) in chloroform (24 ml) and 50% aqueous sodium hydroxide solution (5.4 ml) was added triethylamine (0.1 g, 0.001 mol) and the mixture was vigorously stirred at room temperature for 3.5 h. After addition of water and chloroform, the mixture was stirred, then extracted with chloroform. The extracts were washed with water, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to a residue, which was chromatographed to afford N-methyl-N-benzylcyanamide (1.2 g, 82% yield) as oily substance: NMR(CDCl3) δ 2.77(s, 3H), 4.14(s, 2H), 7.25-7.50(m, 5H); IR(neat) 2220, 1495, 1455, 1365, 730 cm-1.
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]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[C:28]([CH3:35])=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1>>[F:26][C:27]1[C:28]([CH3:35])=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: Cc1c(F)cccc1NN
Product: Cc1c(F)cccc1-n1nccc1-c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (3-fluoro-2-methyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=431.3 (M+H)+
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:11][N:10]=1>C(O)(=O)C>[C:1]([N:11]1[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([OH:8])=[N:10]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C(C)=O)nc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (1.2 mL, 12.8 mmol) is added to a suspension of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (2.0 g, 12.8 mmol) in 30 mL of acetic acid. The reaction mixture is stirred at RT for 2 h. The solvent is removed in vacuo, and the remaining solid is washed with water, collected by vacuum filtration, and dried in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.45 (1H, s), 8.27 (1H, bs), 4.38 (2H, q), 2.64 (3H, s), 1.38 (3H, t).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]([F:45])([F:44])[C:9]1[C:10]([C:35]#[C:36][Si](CC)(CC)CC)=[N:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:13][CH:14]=1>CO.O>[C:35]([C:10]1[C:9]([C:8]([F:44])([F:7])[F:45])=[CH:14][N:13]=[C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[N:11]=1)#[CH:36]
Reactant: CC[Si](C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F)(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of K2CO3 (1.72 g, 12.4 mmol) and tert-butyl 4-(4-((5-(trifluoromethyl)-4-((triethylsilyl)ethynyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate A50 (4.64 g, 8.28 mmol) in MeOH (250 mL) was stirred for 15 minutes at room temperature. The mixture was diluted with water (250 mL) and extracted with DCM (3×250 mL). The organics were combined and adsorbed onto silica gel. Purification by silica gel column chromatography (Biotage Isolera, 0-100% EtOAc in petroleum benzine 40-60° C.) gave the title compound A51 as a yellow solid (2.196 g, 59%). LCMS-A: rt 6.615 min; m/z 445 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:14][O-:15].[Na+]>CO.O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:15][CH3:14])=[N:7]2
Reactant: C[O-]
Reactant: Fc1ccc(Br)c2ccc(Cl)nc12
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(Br)ccc(F)c2n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-bromo-2-chloro-8-fluoroquinoline (1.08 g, 4.2 mmol) in anhydrous methanol (10 mL) at 50° C. was added NaOMe (30% w/w, 0.9 g, 5.0 mmol). The resulting mixture was stirred at 50° C. for one hour, then allowed to cool to room temperature. The mixture was diluted with water, then extracted with EtOAc. The combined organics were washed with water then saturated Nael (aq), dried over MgSO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 0-5% EtOAc/hexanes to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 8.33 (dd, J=9.1, 1.6 Hz, 1H); 7.55 (dd, J=8.4, 4.4 Hz, 1H); 7.22 (dd, J=10.2, 8.4 Hz, 1H); 7.04 (d, J=9.2 Hz, 1H); 4.13 (s, 4H). LC4 2.37 min. (M+H) 256.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl.[NH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(N(CC)CC)C>CN(C=O)C>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1c(C(=O)OCC)c(C(F)(F)F)nc(C(F)(F)Cl)c1C(=O)OC
Yield: 82.4 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.82 g (0.013 mol) of ethyl glycinate hydrochloride, 2.63 g (0.026 mol) of triethylamine in 30 ml of DMF were reacted at room temperature for 16 hours affording a residue which was kugelrohr distilled at 67 Pa, pot temperature 150° C., to give 4.96 g of solid. Recrystallization in hot hexane afforded 4.60 g (75.3%) of product as a beige solid; mp 60°-61.5° C.