Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20](O)=[O:21])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.C(Cl)(=O)C([Cl:28])=O>ClCCl.CN(C=O)C>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([Cl:28])=[O:21])=[CH:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution of 0.43 g (1.22 mmol) of 2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidine-5-carboxylic acid in 8 ml of dichloromethane was treated at RT with 2 drops of DMF. 0.12 ml (1.34 mmol, 1.1 eq) of oxalyl chloride were added within 5 min and stirring was continued for 2 h. The solution was evaporated and dried under reduced pressure to give 0.45 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=1.C(N(CC)CC)C.[CH3:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[NH2:31]>C(O)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:31][C:30]2[CH:32]=[C:33]([CH3:35])[CH:34]=[C:28]([CH3:27])[CH:29]=2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:5]=1
Reactant: CP(C)(=O)c1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Reactant: Cc1cc(C)cc(N)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C)cc(Nc2nc(Cl)nc(Nc3ccc(P(C)(C)=O)cc3)n2)c1

Procedure:
To a solution of 4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 102: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 3,5-dimethylaniline (24 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [CH:1]([CH:4]1[C:8]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([CH3:15])([CH3:14])[O:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[F:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH:30]([F:32])[F:31])[C:25]=1[C:33](Cl)=[O:34]>C(Cl)Cl>[F:32][CH:30]([F:31])[C:26]1[C:25]([C:33]([NH:13][C:9]2[C:8]3[CH:4]([CH:1]([CH3:3])[CH3:2])[O:5][C:6]([CH3:15])([CH3:14])[C:7]=3[CH:12]=[CH:11][CH:10]=2)=[O:34])=[C:24]([F:23])[N:28]([CH3:29])[N:27]=1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: CC(C)C1OC(C)(C)c2cccc(N)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C1OC(C)(C)c2cccc(NC(=O)c3c(C(F)F)nn(C)c3F)c21
Reaction time: 4 h
Yield: 78 %

Procedure:
In a 25 ml round bottom flask, a solution of 3-isopropyl-1,1-dimethyl-1,3-dihydro-2-benzofuran-4-amine (62 mg, 0.301 mmol, 1 eq) in 5 ml of DCM is cooled to 0° C. and triethylamine (0.05 ml, 0.361 mmol, 1.2 eq) is added. A solution of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride (70 mg, 0.331 mmol, 1.1 eq) in 1 ml of DCM is added dropwise. Stirring is allowed for 4 h at r.t. The reaction is quenched with 1N aq. HCl, and diluted with EtOAc. The aqueous layer was separated and extracted with EtOAc. The organics were combined, washed with NaOH 1N, dried over MgSO4 and concentrated. The crude material was purified by chromatography on silica gel to give pure material (78%)
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH2:7][CH2:6]1)=[O:4].CC(O)=O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:7][CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1CC[C@H](CNCCc2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CC[C@H](CNCCc2ccccc2N)CC1

Procedure:
A solution 0.01 M of trans-4-{[2-(2-Nitro-phenyl)-ethylamino]-methyl}-cyclohexanecarboxylic acid methyl ester (2 g, 6.25 mmol) in MeOH (625 mL) with ˜1% of glacial AcOH (6.25 mL) was submitted to continuous flow rate hydrogenation by H-Cube (ThalesNano®) using a 10% Pd/C cartridge (small type cartridge, full hydrogen mode, flowrate of 1 mL/min). Finally, the solvent was removed under reduced pressure to obtain the titles compound (3.07 g, quantitative yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.C(OCC)(=[O:30])C.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][S:2]([C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1)=[O:30]
Reactant: CCCCCC(O)C=CC1C=C(SC)C(=O)C1=CCCCCCC(=O)OC
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCC(O)C=CC1C=C(S(C)=O)C(=O)C1=CCCCCCC(=O)OC
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of 17.6 mg of 2-methylthio-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone obtained in Example 34 in methanol (0.5 ml) was added a solution of 2KHSO5 ·KHSO4 ·K2SO4 (27.4 mg) in water (0.2 ml) at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogencarbonate, and the product was extracted into the organic layer. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered, followed by concentration. The concentrate was subjected to silica gel chromatography to obtain 3 mg (yield 16%) of 2-methylsulfinyl-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:30](#[N:32])[CH3:31]>CC(N(C)C)=O.O>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:31]4[CH:30]=[N:32][C:8]([NH2:10])=[N:5][CH:4]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC#N
Reactant: CC1CCN(C(=O)N2CCOc3ccc(B(O)O)cc3C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC1CCN(C(=O)N2CCOc3ccc(-c4cnc(N)nc4)cc3C2)CC1
Temperature: 95 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 2-amino-5-bromopryimidine (65 mg, 0.37 mmol), {4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-yl}boronic acid (100 mg, 0.31 mmol) and potassium carbonate (215 mg, 1.6 mmol) in DMA (5.0 mL) and water (0.5 mL) was added dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (23 mg, 0.03 mmol). The reaction mixture was stirred at 95° C. for 2.5 hours and then partitioned between dichloromethane (10 mL) and 1M aqueous sodium hydroxide (10 mL). The organic layer was separated and washed with brine (10 mL) then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel using 2% methanol in dichloromethane as eluent and the combined product containing fractions were concentrated. The residue thus obtained was taken into a minimum of acetonitrile and purified by preparative reverse phase HPLC to afford 5-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}pyrimidin-2-amine (24 mg) as an amorphous solid. 1H NMR (400 mHz, DSMO-d6): 8.51 (s, 2H), 7.47 (d, 1H), 7.42 (dd, 1H), 6.98 (d, 1H), 6.75 (s, 2H), 4.39 (s, 2H), 4.12-4.18 (m, 2H), 3.46-3.59 (m, 4H), 2.70 (t, 2H), 1.42-1.61 (m, 3H), 1.04-1.18 (m, 2H), 0.91 (d, 3H); MS (EI) for C20H25N5O2: 368 (MH+).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:36])[CH3:35])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:45][C:40]1[CH:39]=[C:38]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:35])[CH3:36])[CH:28]=3)[CH2:21]2)[CH:43]=[CH:42][C:41]=1[Cl:44]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CC(C)Oc1cccc(CC(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)c1
Solvent: CC#N
Product: CC(C)Oc1cccc(CC(=O)N2CC[C@@](CCN3CCC(N4CCCCC4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl)pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum an the residue is taken up in methylene chloride and washed with a 3 N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])OC4C=CC=CC=4)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[CH2:32]([O:34][CH:35]([O:38][CH2:39]C)[CH2:36][NH2:37])C>O1CCOCC1>[CH3:32][O:34][CH:35]([O:38][CH3:39])[CH2:36][NH:37][C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)=[CH:21][CH:20]=1)=[O:31]
Reactant: CCOC(CN)OCC
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(c3ccc(NC(=O)NCC(OC)OC)cc3)CC2)cc1

Procedure:
A mixture of 10 parts of phenyl [4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]carbamate monohydrochloride (described in example XVII of U.S. Pat. No. 4,267,179), 3 parts of 2,2-diethoxy-ethanamine and 100 parts of 1,4-dioxane was stirred for 6 hours at reflux temperature. After cooling, the precipitate was filtered off, washed with 1,4-dioxane and purified by column chromatography (silica gel; CHCl3 /CH3OH 99:1). The eluent of the desired fraction was evaporated and the residue was crystallized from 1,4-dioxane, yielding 3.9 parts of N-(2,2-dimethoxyethyl)-N'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]urea; mp. 225° C. (interm. 8).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:11]([C:19]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20]3)[O:10][N:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:29][O:30][CH2:31][CH2:32]O>C(OCC)(=O)C>[CH3:29][O:30][CH2:31][CH2:32][O:23][C:22]([C:19]1([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:21][CH2:20]1)=[O:24]
Reactant: COCCO
Reactant: O=C(O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COCCOC(=O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Temperature: 60 °C

Procedure:
To a solution consisting of the product of Example 87 (0.50 g) in 2-methoxyethanol (5 mL) is added thionyl chloride (1.0 mL.) The mixture is heated to 60° C. for 18 h is and is subsequently cooled, diluted with ethyl acetate, washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with a gradient (0 to 50% ethyl acetate in hexanes) afforded the title compound (0.37 g); MS (APCI+) m/z 380 (MH+.)
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]=[O:19])[CH2:14][CH2:13]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][C:7]1[O:8][C:9]([CH:18]([CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[OH:19])=[CH:10][CH:11]=1
Reactant: Cc1ccco1
Reactant: O=CC1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C2CCOCC2)o1
Temperature: -70 °C
Reaction time: 2 h
Yield: 112.9 %

Procedure:
12.0 ml (30 mmol, 1.5 eq) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution of 2.46 g (30 mmol, 1.5 eq) of 2-methylfuran in 50 ml of tetrahydrofuran cooled to −70° C. The reaction medium was stirred and allowed to return to ambient temperature for 2 hours. The reaction medium was cooled to −70° C. and then 2.28 g (20 mmol, 1 eq) of tetrahydro-2H-pyran-4-carbaldehyde were added. The reaction medium was stirred at ambient temperature for 2 hours. The reaction medium was treated with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution and evaporated. 4.43 g of (5-methylfuran-2-yl)-(tetrahydropyran-4-yl)methanol were obtained. Yield=100%.
Reaction SMILES: N1C2CCNCCC=2C=C[CH:2]=1.[Br:12][C:13]1[CH:14]=[N:15][C:16]2[N:17]([N:19]=[C:20]([C:22]([N:24]3[CH2:30][CH2:29][C:28]4[N:31]=[CH:32][NH:33][C:27]=4[CH2:26][CH2:25]3)=[O:23])[CH:21]=2)[CH:18]=1.CI.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:12][C:13]1[CH:14]=[N:15][C:16]2[N:17]([N:19]=[C:20]([C:22]([N:24]3[CH2:30][CH2:29][C:28]4[N:31]=[CH:32][N:33]([CH3:2])[C:27]=4[CH2:26][CH2:25]3)=[O:23])[CH:21]=2)[CH:18]=1
Reactant: O=C(c1cc2ncc(Br)cn2n1)N1CCc2nc[nH]c2CC1
Reactant: c1cnc2c(c1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cnc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
75.0 mg (0.21 mmol) 6 (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl)-methanone, 13.0 μL (0.21 mmol) methyliodide, 35.0 mg (0.25 mmol) potassium carbonate in 1.0 mL DMF were stirred at RT overnight. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 12 mg (15% of theory). ESI-MS: m/z=375 (M+H)+; Rt(HPLC): 0.71 min. (Method K).
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH2:23])=[NH:22])=[CH:16][CH:15]=1)#[N:13].[Na]>C(O)C>[OH:9][C:1]1[CH:2]=[C:3]([OH:5])[N:23]=[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)[N:22]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N#Cc1ccc(NC(=N)N)cc1
Agent: [Na]
Solvent: CCO
Product: N#Cc1ccc(Nc2nc(O)cc(O)n2)cc1
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
Diethyl malonate (30 gm) was added to 1-(4-cyanophenyl)guanidine (30 gm) at room temperature. A solution of sodium (17.2 gm) in ethanol (450 ml) was added to the above reaction mass. The contents were heated to reflux and maintained for 12 hours. Distilled off the solvent completely under vacuum and then added water (500 ml). The reaction mass was stirred for 30 minutes and filtered. The solid obtained was dried to obtain 40 gm of 4-(4,6-dihydroxypyrimidine-2-yl-amino)benzonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH2:29])[CH2:27][CH3:28])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH:29][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][CH3:28])=[N:25][C:21]=2[CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Reactant: CC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(C)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propylamine, TBTU and DIPEA in THF.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([O:19][CH3:20])[C:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[C:12]3[Cl:32])([OH:8])[C:6]#[CH:7])[CH2:2]1.CCN(CC)CC.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[Cl:32][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:5]([CH:3]3[CH2:4][N:1]([C:40](=[O:42])[CH3:41])[CH2:2]3)([OH:8])[C:6]#[CH:7])[CH:10]=2)[N:15]=[C:14]([O:19][CH3:20])[C:13]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1
Reactant: CC(=O)OC(C)=O
Reactant: C#CC(O)(c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1)C1CNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(O)(c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1)C1CN(C(C)=O)C1
Temperature: 40 °C

Procedure:
To a flask containing crude 1-(azetidin-3-yl)-1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)-benzyl)quinolin-6-yl)prop-2-yn-1-ol (130 mg, 0.28 mmol, Example 16) was added DCM (10 mL) followed by Et3N (0.2 mL, 1.44 mmol) and acetic anhydride (0.1 mL, 1.06 mmol) at room temperature. The mixture was heated to 40° C. for 2 hours and then quenched with a solution of saturated aqueous NaHCO3. The aqueous portion was extracted with DCM (3×35 mL) and the combined organics were dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel using (5% MeOH-DCM) provided the title compound as an off white amorphous solid. 1H NMR (500 MHz, CD3OD) δ 8.44 (d, J=1.9 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.91-7.82 (m, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 4.40 (s, 2H), 4.36-4.18 (m, 1H), 4.16-4.01 (m, 4H containing a singlet at 4.07), 4.05-3.98 (m, 1H), 3.93-3.80 (m, 1H), 3.28 (s, 1H), 3.24-3.09 (m, 1H), 1.85 (d, J=3.3 Hz, 3H); MS (ESI): mass calcd. for C26H22ClF3N2O3, 502.1, m/z found 503.2 [M+H]+. 1-(3-(1-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-hydroxyprop-2-yn-1-yl)azetidin-1-yl)ethanone was purified by chiral SFC: (Stationary phase: CHIRALPAK AD-H, 5 μm, 250×20 mm), Mobile phase: 70% CO2, 30% MeOH), to give 2 enantiomers. The first eluting enantiomer was Example 7b and the second eluting enantiomer was Example 7c.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=3)[C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH:32]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]1>C(Cl)Cl.CN(C=O)C>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([N:32]4[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]4)=[O:18])=[CH:15][CH:14]=3)[C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCNC1
Reactant: O=C(O)c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1)N1CCC(O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2-phenyl-benzoimidazol-1-ylmethyl)-benzoic acid (1 g, 3 mmol) in DCM is treated with 2 drops of DMF followed by oxalylchloride (3 mL, 6 mmol, 2M solution in DCM), stirred at room temperature for 2 hours and concentrated in vacuo. The resultant residue is dissolved in DCM, treated with 3-pyrrolidinol (0.3 mL, 3.6 mmol), stirred at room temperature for 8 hours then concentrated to give 1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]benzoyl}pyrrolidin-3-ol identified by HPLC and MS [398.4 m/e (M+H)].
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:31])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([F:21])=[CH:15][N:14]=3)=O)CCCCC1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:41]>>[Cl:41][C:19]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([F:21])[CH:17]=2)[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:11](=[O:31])[C:10]=1[C:8]#[N:7]
Reactant: COc1ccc(Cn2c(=O)c(C(=O)NC3CCCCC3)c(O)c3cc(F)cnc32)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)c(C#N)c(Cl)c3cc(F)cnc32)cc1
Yield: 69 %

Procedure:
A solution of 6-fluoro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid cyclohexylamide (92) (7.46 g, 17.53 mmol) and triethylamine (6.1 mL, 43.83 mmol) was heated in neat POCl3 overnight at 90° C. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in saturated NaHCO3 solution, sonicated briefly and filtered. The solids were dissolved in dichloromethane, washed subsequently by saturated NaHCO3 solution, water and brine. The organic phase was dried over MgSO4 and evaporated to yield 4.2 g (69%) of 4-chloro-6-fluoro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (94) as white solids. MP 195° C. 1H-NMR (DMSO-d6): δ 3.69 (s, 3H), 5.51 (s, 2H), 6.82 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H), 8.48 (dd, J=2.8, 8.4 Hz, 1H), 8.96 (d, J=2.8 Hz, 1H); EIMS m/z 344 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1.[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42]([O:44][CH3:45])=[O:43])#[CH:34].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[CH3:45][O:44][C:42](=[O:43])[CH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:33]#[C:34][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 30 %

Procedure:
tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I94) (0.500 g, 1.06 mmol) and methyl 2-(2-ethynylphenyl)acetate (I4) (0.203 g, 1.17 mmol) were dissolved in DMF (10 mL) and bis(triphenylphosphine)palladium(II) chloride (37 mg, 5 mol %) was added. The mixture was degassed with nitrogen for ten minutes, then copper(I) iodide (10 mg, 5 mol %) and triethylamine (0.738 mL, 5.30 mmol) were added. The mixture was heated under microwave irradiation (100° C./20 minutes) then concentrated. Chromatography of the residue (12 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I95) (192 mg, 30% yield) as a brown oil;
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)[C:7]1=[O:18])[CH3:4].[C:19]1([N:25]2[C:29]3([CH2:34]CNC[CH2:30]3)[C:28](=[O:35])[NH:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:19]1([N:25]2[C:29]3([CH2:30][CH2:2][N:3]([CH2:5][CH:6]4[CH2:15][CH2:14][C:13]5[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=5)[C:7]4=[O:18])[CH2:4][CH2:34]3)[C:28](=[O:35])[NH:27][CH2:26]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: COc1ccc2c(c1)C(=O)C(CN(C)C)CC2
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)C(=O)C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
A mixture of 15.0 g of 2-[(dimethylamino)methyl]-3,4-dihydro-7-methoxy-1(2H)-naphthalenone, hydrochloride (1:1), 13.0 g of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, and 250 ml of absolute ethanol is heated on a steam bath until all solids dissolve. The resulting solution is stirred for 16 hours at room temperature under nitrogen. The resulting precipitates are collected and washed with additional absolute ethanol to give 16.7 g of the title compound.