Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH:13]=[N:14][OH:15].[CH:16]1([N:22]=[C:23]=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>CN(C)C=O>[CH:16]1([NH:22][C:23](=[O:15])[OH:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH:13]=[N:14][OH:15]
Reactant: O=C=NC1CCCCC1
Agent: ON=Cc1c(Cl)ccc2cc(Cl)cnc12
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)NC1CCCCC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
24 g of 3,7-dichloroquinoline-8-aldoxime were dissolved in 250 ml of dimethylformamide, 12.5 g of cyclohexyl isocyanate were added dropwise at room temperature and the solution was then stirred at 50° C. for 5 hours. In the course of the reaction period, a further 12 g of cyclohexyl isocyanate were slowly added dropwise. 2 liters of water were added to the reaction solution, and the solid was filtered off under suction, suspended in a little methanol, again filtered off under suction and recrystallized from toluene with active carbon to give 26 g (72% of theory) of 3,7-dichloroquinoline-8-aldoxime cyclohexylcarbamate of melting point 152° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[CH:22]=[C:21]([CH:23]([F:25])[CH3:24])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:25][CH:23]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[CH:22]=1)[CH3:24]
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: CC(F)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(F)c1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 112 mg, 0.521 mmol), 4-chloro-6-(1-fluoroethyl)pyrimidine (Intermediate 21, 125 mg, 0.781 mmol) and DIPEA (0.182 mL, 1.041 mmol) were added together in N-methyl-2-pyrrolidone (3 mL) and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was heated at 100° C. for 1 hour and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (25 mg);
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17](O)=[O:18])[CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Cl.[NH2:23][C@H:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)[CH3:25].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.CN(C=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:23][C@H:24]([C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)[CH3:25])=[O:18])[CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cccc2c1N(Cc1ccc(Cl)cc1)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3c2N(Cc2ccc(Cl)cc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.1 %

Procedure:
A mixture of 1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinoline-8-carboxylic acid (310 mg), methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (240 mg), EDCI.HCl (210 mg), HOBt (160 mg), pyridine (0.25 mL), and DMF (3.00 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain methyl 4-[(1S)-1-({[1-(4-chlorobenzyl)-1,2,3,4-tetrahydroquinolin-8-yl]carbonyl}amino)ethyl]benzoate (129 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:11]([N:28]2[CH2:33][CH2:32][NH:31][C@H:30]([CH3:34])[CH2:29]2)[N:10]=1.Br[CH2:36][C:37]([NH2:39])=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([N:28]2[CH2:33][CH2:32][N:31]([CH2:36][C:37]([NH2:39])=[O:38])[C@H:30]([CH3:34])[CH2:29]2)[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:13]([CH3:15])[N:14]=1
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1N1CCN[C@H](C)C1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(-c2c(C)cccc2C)nc1N1CCN(CC(N)=O)[C@H](C)C1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methyl-6-[(3R)-3-methylpiperazin-1-yl]pyrimidine (32 mg, 0.07 mmol), 2-bromoacetamide (29 mg, 0.21 mmol), sodium carbonate (44 mg) and DMA (1 mL) is heated at 60° C. under nitrogen with magnetic stirring for 18 h. The reaction mixture is allowed to cool and partitioned between EtOAc (8 mL) and water (2 mL). The organic layer is separated, washed with water (2 mL), brine (2 mL), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a colorless oil. Purification by chromatography on silica gel (2% MeOH/DCM/0.1% Ammonium hydroxide) provides the title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.06-7.26 (m, 5H), 6.81-6.83 (m, 2H), 5.58 (br, d, J=6.3 Hz, 1H), 4.97 (dd, 2H), 3.77-3.86 (m, 2H), 3.25-3.33 (m, 2H), 2.80-3.00 (m, 4H), 2.45-2.62 (m, 5H), 2.22 (s, 3H), 2.16 (s, 6H), 1.27 (d, J=6.8 Hz, 6H), 0.93 (d, J=6.6 Hz, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:5](/[CH:12]=[C:13]2\[C:14](=[O:22])[NH:15][C:16]3[C:21]\2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:4]1.[H][H].I[CH3:26]>CN(C=O)C>[CH3:26][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:5](/[CH:12]=[C:13]2\[C:14](=[O:22])[NH:15][C:16]3[C:21]\2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:4]1
Reactant: CI
Reactant: O=C1Nc2ccccc2/C1=C/c1c[nH]c2ncccc12
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(/C=C2\C(=O)Nc3ccccc32)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a suspension of 95% sodium hydride (0.280 g, 0.011 mol) in DMF (100 ml) cooled with an ice-n-propanol bath is added over 15 min with stirring a solution of (Z)-3-[(7-azaindol-3-yl)methylen]-2-oxindole (2.61 g, 0.010 mol) in DMF (50 ml). When the evolution of hydrogen stopped, a solution of iodomethane (1.56 g, 0.011 mol) in DMF (50 ml) is added over 15 min and the mixture is stirred at r.t. for 3 h. Most of the DMF is distilled off in vacuo, water is then added to the residue and the product extracted into ethyl acetate. The organic solution containing the desired product is dried (Na2SO4), the solvent evaporated and the remaining oil is crystallized by trituration with ethanol. Thus pure title compound is obtained in 60% yield. C17H13N3O requires : C 74.19 H 4.73 N 15.27 found : C 74.05 H 4.55 N 15.05 MS m/z : 275.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22])#[CH:18]>CN(C=O)C.CC(N(C)C)=O>[C:17]([C:19]1[CH:20]=[C:21]([NH:22][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:23]=[CH:24][C:25]=1[F:26])#[CH:18]
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Reactant: C#Cc1cc(N)ccc1F
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: C#Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1F
Temperature: 25 °C
Reaction time: 45 h
Yield: 84.7 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.65 g, 10.0 mmol), thionyl chloride (20 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 1 h to give a homogeneous mixture. It was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 3-ethynyl-4-fluoroaniline (J. Org. Chem., 1981, 46, 2280-2286) (1.49 g, 11.0 mmol) and dry DMA (15 mL). The residue of 3-ethynyl-4-fluoroaniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 45 h. It was poured into water (300 mL). The pH was adjusted to ca. 9 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether (300 mL). The solid was collected by filtration and washed with water (5×50 mL); ethyl acetate/petroleum ether (1:10) (4×50 mL) and dried to give N-(3-ethynyl-4-fluorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (208) (2.39 g, 85%) as a pale brown solid, mp 223-226° C.; 1H NMR δ [(CD3)2SO] 10.10 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 8.24 (br s, 1H),), 8.12 (dd, J=6.4, 2.8 Hz, 1H), 7.96-7.88 (m, 1H), 7.39 (t, J=9.1 Hz, 1H), 4.54 (s, 1H). Anal. Calcd for C15H8F2N4.1.8H2O: C, 57.25; H, 3.72; N, 17.80. Found C, 57.27; H, 3.49; N, 17.90.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[O:24])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1cccnc1
Product: CCN(Cc1cccnc1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[C:27](=[O:28])[CH2:26][C@H:25]5[NH:29][C@H:22]([CH2:23][CH2:24]5)[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH2:36]=O>>[CH3:1][NH:2][C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[C:27](=[O:28])[CH2:26][C@H:25]5[N:29]([CH3:36])[C@H:22]([CH2:23][CH2:24]5)[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: C=O
Reactant: CNC(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Product: CNC(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5C)cn3)nc2n1C1CCCC1
Yield: 98 %

Procedure:
Following general reductive alkylation method 1, 7-cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide was combined with formaldehyde which gave 7-cyclopentyl-2-[5-((1R,6S)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide (100 mg) in 98% yield.
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH2:14]([OH:18])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: CC(C)COc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of sodium (230 mg, 10 mmol) in isobutanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50° C. for 3 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: C[Li].C(NC(C)C)(C)C.[C:10]1([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>C(OCC)C>[CH2:20]([O:19][C:17]([O:18][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:21]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)Cc1ccccc1
Agent: [Li]C
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CCOC(=Cc1ccccc1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
Methyllithium in diethyl ether (0.25 mol, 140 ml of 1.8 M solution) was added dropwise to a solution of 27.6 g (0.27 mol) of diisopropylamine in 40 ml of diethyl ether. The reaction mixture was cooled to -78° C. and 26.3 g (0.16 mol) of ethyl phenylacetate were added dropwise. The reaction mixture was warmed to 0° C. and 46 ml (0.36 mol) of chlorotrimethylsilane were added rapidly. The reaction mixture was stirred overnight at 25° C., filtered to remove LiCl, and then distilled under reduced pressure to give 24.91 g (66% yield) of β-ethoxy-β-trimethylsiloxystyrene as a colorless liquid: bp 92° C. (0.7 mm); 1H NMR (CFCl3) δ 0.0 ppm (s, 9H), 0.94 ppm (t,J=7 Hz, 3H), 3.44 and 3.63 ppm (qs, J=7 Hz, 25:75, 2H), 4.17 and 4.36 ppm (ss, 25:75, 1H) and 6.57-7.20 ppm (m, 5H). Anal. Calcd. for C13H20O2Si: C, 66.05; H, 8.53; Found: C, 66.26; H, 8.88.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][N:4]=1.C[Li].CN([CH:18]=[O:19])C>C1COCC1.C(NC(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][N:4]=1)[CH:18]=[O:19]
Reactant: COCOc1ccc(OC)nc1
Reactant: CN(C)C=O
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCOc1cnc(OC)cc1C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
To a mixture of 2-methoxy-5-(methoxymethoxy)pyridine (30 g, 0.178 mol, 1 eq.) and diisopropylamine (507 uL, 3.6 mmol, 0.02 eq.) in THF (500 mL) was added methyl lithium (1.6 M/THF, 200 mL, 0.32 mol, 1.8 eq.) at −40° C. Upon the completion of addition, the mixture was warmed to 0° C., continued to stir at 0° C. for 3 h, cooled back down to −40° C. and added DMF (24.7 mL, 0.32 mol, 1.8 eq.) slowly. The mixture was then stirred at −40° C. for 1 h, quenched with a mixture of HCl (12 N, 120 mL) and THF (280 mL), warmed to rt, and added water (200 mL). The pH of the mixture was adjusted to pH 8-9 with solid K2CO3. The aqueous layer was extracted with EtOAc (300 mL) twice. The combined organic layers were dried over Na2SO4 and concentrated to give 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 95.7%) as a brown solid, which was used for next step without further purification. 1H NMR (400 MHz; CD3OD) 7.90 (s, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 5.20 (s, 2H), 3.84 (s, 3H), 3.48 (s, 3H). LRMS (M+H+) m/z 198.1
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH3:18])[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: COc1ccccc1B(O)O
Product: COC(=O)c1c(O)c2ccc(-c3ccccc3OC)cc2sc1=O

Procedure:
4-Hydroxy-7-(2-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) and 2-methoxyphenylboronic acid under conditions analogous to Example 7(a). MS ESI(−) m/e: 341.07 (M−1).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C@@H:19]([NH3+:21])[CH3:20])=[N:7]2.Cl[C:23]1[C:24]2[C:31]([S:32][C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[O:40][CH3:41])=[CH:30][N:29]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:25]=2[N:26]=[CH:27][N:28]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[F:39][C:37]1[CH:36]=[CH:35][C:34]([O:40][CH3:41])=[C:33]([S:32][C:31]2[C:24]3[C:23]([NH:21][C@H:19]([C:8]4[N:9]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)[C:10](=[O:12])[C:11]5=[C:3]([CH3:2])[CH:4]=[CH:5][N:6]5[N:7]=4)[CH3:20])=[N:28][CH:27]=[N:26][C:25]=3[N:29]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[CH:30]=2)[CH:38]=1
Reactant: COc1ccc(F)cc1Sc1cn(COCC[Si](C)(C)C)c2ncnc(Cl)c12
Reactant: Cc1ccn2nc([C@H](C)[NH3+])n(-c3ccccc3)c(=O)c12
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1ccc(F)cc1Sc1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Temperature: 125 °C
Yield: 72.1 %

Procedure:
(S)-1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethanaminium chloride (39 mg, 0.13 mmol) was treated with 4-chloro-5-((5-fluoro-2-methoxyphenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (56 mg, 0.13 mmol), cesium fluoride (8 mg, 0.05 mmol), N,N-diisopropylethylamine (201 μl, 1.15 mmol) and tert-butanol (0.78 ml) as a solvent according to Preparation 13 but heating the reaction mixture at 125° C. overnight. The residue was purified using SP1® Purification System (0% to 40%, hexane-ethyl acetate) to give 63 mg (73% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[N:5]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=1.[C:19]1([N:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>CN(C)C=O>[Cl:12][C:10]1[CH:9]=[C:8]([Cl:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:1][C:26]([N:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27])=[CH:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5]2
Reactant: CCOC(=O)c1cc(N)c2c(Cl)cc(Cl)cc2n1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(NC(=O)N(c2ccccc2)c2ccccc2)c2c(Cl)cc(Cl)cc2n1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
5-L three-neck flask was charged with a cold (<10° C.) solution of Compound 5 (about 0.59 mole, 168.95 g) in N,N-dimethylformamide (DMF) (about 2 L). Diphenylcarbamoyl chloride (0.73 mole, 168.92 g) then was added to the solution. The resulting mixture was maintained below 10° C., sodium hydride (NaH; 1.19 mole, 28.45 g) was added, in portions, over about 1.3 hours, and the reaction mixture was allowed to warm to ambient temperature overnight. Thin layer chromatography (TLC) indicated that some unreacted Compound 5 remained. The reaction mixture was recooled to about 10° C., and additional NaH (about 0.3 mole, 7.11 g) was added. The subsequent reaction was quenched with saturated aqueous ammonium chloride (NH4Cl; about 1.3 L) followed by the addition of 10% aqueous acetic acid (AcOH; 1 L), 20% AcOH (0.5 L), and EtOAc (4 L) to obtain a mixture having a pH of about 4 to 5. The solids present in the flask then were filtered, rinsed with EtOAc (500 mL) and DI water (500 mL), and dried by lyophilization to afford about 229 g of crude Compound 6 and a crude filtrate containing additional Compound 6. The crude Compound 6 was dissolved in dichloromethane (CH2Cl2; 3 L), back extracted with deionized (DI) water (500 mL) and brine (500 mL). The organic phase was dried over Na2SO4 (323.30 g) and filtered to afford a solution containing the bulk of the crude Compound 6.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]#[CH:11].C[Mg+].[Br-].[CH2:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH:23]=[O:24])[CH2:19][CH2:18]1)[CH3:16].Cl>O1CCCC1>[CH2:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH:23]([OH:24])[C:11]#[C:10][C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[CH2:19][CH2:18]1)[CH3:16]
Reactant: CC[C@H]1CC[C@H](C=O)CC1
Reactant: C#Cc1ccc(F)c(F)c1F
Agent: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: CC[C@H]1CC[C@H](C(O)C#Cc2ccc(F)c(F)c2F)CC1
Reaction time: 1 h

Procedure:
Into the tetrahydrofuran (THF) (100 ml) solution containing 2,3,4-trifluorophenylacetylene (20 g), the THF solution (93 ml) of 1.5 M bromide methyl magnesium was added dropwise at 0° C., and stirred for 1 hour. Into this, the THF (50 ml) solution of trans-4-ethylcyclohexane carboaldehyde (18 g) was added dropwise, and stirred for 1 hour. The reaction solution was poured into 5% hydrochloric acid, extracted with ethyl acetate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain 1-(trans-4-ethylcyclohexyl)-3-(2,3,4-trifluorophenyl)-2-propyne-1-ol (38 g).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][CH:29]([NH2:31])[CH3:30]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:31][CH:29]([CH3:30])[CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CC(C)N
Solvent: CC#N
Product: CC(C)NC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), propan-2-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 319 (M+, 1), 304 (8), 84 (8), 73 (6), 72 (bp), 56 (7).
Reaction SMILES: ClCCl.[CH2:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:5].C(O)(=O)C.[I:22]I>FC(F)(F)S([O-])(=O)=O.[Ag+].C(OCC)(=O)C>[CH2:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([I:22])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH3:5]
Reactant: CCN1CCC(c2ccccc2)CC1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN1CCC(c2ccc(I)cc2)CC1
Reaction time: 8 h

Procedure:
A dichloromethane (36 mL) mixture of 1-ethyl-4-phenylpiperidine (1.37 g, 7.23 mmol), acetic acid (500 μL), silver trifluoromethanesulfonate (3.72 g), and iodine (3.67 g) was stirred overnight. Ethyl acetate was added, then the insoluble matter was removed by filtration. The obtained filtrate was washed with ammonia water, aqueous sodium thiosulfate solution and saturated saline. After dried with anhydrous magnesium sulfate, this was concentrated and purified by flash column chromatography (FPNH, hexane:ethyl acetate=1 to 9:1) to obtain a mixture of the entitled compound and 1-ethyl-4-phenylpiperidine (2.52 g).