Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[H-].[Na+].[C:12]1([CH:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][CH2:20][O:21][C:22](=[O:28])[CH2:23][C:24]([CH2:26]Cl)=[O:25])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>C1COCC1>[C:12]1([CH:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:19][CH2:20][O:21][C:22](=[O:28])[CH2:23][C:24](=[O:25])[CH2:26][O:9][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CCl)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: OCCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(COCCc1ccccn1)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
503 mg (4.08 mmol) of 2-(pyridine-2-yl)ethanol was added dropwise to a suspension of 326 mg (8.16 mmol) of sodium hydride (60% oily) in 10 ml of THF at 0° C., and they were stirred for 30 minutes. A solution of 0.90 mg (2.72 mmol) of (3,3-diphenylpropane-1-yl)4-chloroacetoacetate in 3 ml of THF was added dropwise to the reaction mixture, and they were stirred at room temperature overnight. After the addition of methanol, the reaction mixture was concentrated and fractionated with ethyl acetate and water. After the drying over sodium sulfate followed by the purification by the silica gel chromatography (methylene chloride/methanol=100/1), the title compound was obtained.
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([C:6]1[C:7]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[CH:14]=1)[CH2:4][CH3:5]>C(O)C>[CH2:3]([C:6]1[C:7]([CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[CH:14]=1)[CH2:4][CH3:5].[Na+:2]
Reactant: CCCc1cc2c(cc1CCC(=O)O)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cc2c(cc1CCC(=O)[O-])OCO2

Procedure:
29.2 ml of a 1N aqueous sodium hydroxide solution and 100 ml of ethanol were added to 6.9 g of 3-(6-propyl-1,3-benzodioxole-5-yl)propionic acid to obtain a solution. The solvent was distilled off and ether was added to the residue. A precipitation thus formed was recovered by filtration and dried to obtain 7.5 g of the intended compound in the form of a colorless powder.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[CH:13][CH:14]=2)[CH:9]([NH2:22])[CH2:8][CH:7]1[CH3:23])(=[O:5])[CH3:4].CCN(C(C)C)C(C)C.Cl[C:34]1[N:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1>CN1C(=O)CCC1>[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[CH:13][CH:14]=2)[CH:9]([NH:22][C:34]2[N:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)[CH2:8][CH:7]1[CH3:23])(=[O:5])[CH3:4]
Reactant: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2C(N)CC1C
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2C(Nc2ccc(C#N)cn2)CC1C
Temperature: 25 °C
Yield: 11 %

Procedure:
A solution of 1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinamine di-hydrochloride (for a preparation see intermediate 61) (85 mg, 0.299 mmol) in NMP (2 mL) was treated with DIPEA (0.209 ml, 1.196 mmol), then 6-chloro-3-pyridinecarbonitrile (49.7 mg, 0.359 mmol) and the resulting mixture was heated at 200° C. for 30 min under microwave irradiation, then cooled to room temperature and the solution purified by MDAP to give 6-{[1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]amino}-3-pyridinecarbonitrile (12.2 mg, 0.032 mmol, 11% yield) as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:24]C(=O)OCC2C=CC=CC=2)[C:18]([C@@:20]2([CH3:23])[CH2:22][O:21]2)=[O:19])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>CO>[OH:41][C:35]([C:37]([F:40])([F:39])[F:38])=[O:36].[NH2:24][C@H:17]([C:18]([C@@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCc1ccc(C[C@H](N)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.17 h

Procedure:
Cbz-protected amine 14 (107 mg, 0.23 mmol) was dissolved in MeOH (5 mL) and to this was added TFA (1.2 eq., 0.27 mmol, 21 μL). Argon was bubbled through the solution for 15 minutes, after which Pd black (10 mg) was added and the flask was charged with hydrogen gas. After 10 minutes, TLC analysis indicated complete conversion of starting material and all solids were removed by filtration over CELITE. Toluene (10 mL) was added and the mixture was concentrated under reduced pressure followed by coevaporation with toluene (2×) in order to remove excess TFA. The purity of the deprotected amine (as TFA salt) was confirmed by LC-MS analysis and the compound was subjected to the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:21]([O:23][C@@H:24]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]>>[CH2:21]([O:23][C@@H:24]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:19][CH2:18]/[CH:17]=[C:16](/[C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)\[CH3:20])=[CH:35][CH:36]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]
Reactant: C/C(=C\CO)c1ccc(-c2ccc(C(C)C)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(C(C)C)cc3)cc2)cc1)OCC
Yield: 84.3 %

Procedure:
The title compound (410 mg, 84%) was prepared as a colourless solid from (E)-3-(4′-isopropyl-biphenyl-4-yl)-but-2-en-1-ol (266 mg, 1.00 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (250 mg, 1.05 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1)=O.[F:20][C:21]([F:26])([F:25])[CH2:22][NH:23][NH2:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][C:9]1[CH:8]=[C:7]([C:5]2[N:23]([CH2:22][C:21]([F:26])([F:25])[F:20])[N:24]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=2)[CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1[N+](=O)[O-]
Reactant: NNCC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cc(C(F)(F)F)nn2CC(F)(F)F)ccc1[N+](=O)[O-]
Yield: 21.6 %

Procedure:
A toluene solution of 4,4,4-trifluoro-1-(3-methyl-4-nitro-phenyl)-butane-1,3-dione (1.8 g), 2,2,2-trifluoroethylhydrazine (1.2 g) and a catalytic amount of p-toluenesulfonic acid were refluxed for 6 hours. After cooling, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 3-(3-methyl-4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-5-trifluoro-methyl-1H-pyrazole (IX-5) (1.1 g) and 5-(3-methyl-4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-3-trifluoromethyl-1H-pyrazole (1-6) (0.5 g), respectively.
Reaction SMILES: [CH2:1]([N:4]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C:5]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:20](=[O:42])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([NH:31][C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])=[NH:30])=[CH:25][CH:24]=3)[CH2:13][C@:14]([CH2:16][C:17](O)=[O:18])([CH3:15])[C:8]2=[N:7][CH:6]=1)[CH:2]=[CH2:3].[NH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1>>[CH2:46]([O:45][C:43](=[O:44])[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:20](=[O:42])[NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([NH:31][C:32]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[NH:30])=[CH:27][CH:28]=3)[CH2:13][C@@:14]([CH3:15])([CH2:16][C:17](=[O:18])[N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[C:8]2=[N:7][CH:6]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: C1CCNCC1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)CC(=O)O
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)CC(=O)N1CCCCC1
Yield: 72.5 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 18 g, intermediate 39a (20 mg, 0.028 mmol) was coupled with piperidine (8.1 mg, 0.14 mmol) to provide 15.7 mg (71%) of intermediate 41a. MS (ESI) 774.5 (M+H+).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14]([OH:18])[CH2:15][C:16]#[CH:17]>C(N(CC)CC)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>[OH:18][CH2:14][CH2:15][C:16]#[C:17][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C#CCCO
Reactant: COC(=O)c1cccc(OC)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(OC)c1C#CCCO
Yield: 14.7 %

Procedure:
A mixture of methyl 2-bromo-3-methoxybenzoate (0.4 g, 1.63 mmol), Pd(PPh3)2Cl2 (0.057 g, 0.082 mmol), copper (I) iodide (0.031 g, 0.16 mmol) and 3-butyn-1-ol (0.173 ml, 2.28 mmol) were stirred in trietylamine (5 ml) at 80° C. for 20 h. The solvent was concentrated under vacuum, and the residue was partitioned between ethyl acetate (15 ml) and water (5 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using hexanes:ethyl acetate 2:1 as eluent to afford methyl 2-(4-hydroxybut-1-yn-1-yl)-3-(methyloxy)benzoate (0.056 g; 15% yield). MS (EI) for C13H14O4: 235 (MH+).
Reaction SMILES: [C:1]1(/[C:7](/[C:31]#[C:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:8]\[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:30])[C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>N1C2C(=CC=CC=2)C=CC=1.CO>[C:1]1(/[C:7](/[CH:31]=[CH:32]\[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:8]/[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:30])[C:18]3[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=3)[CH2:15][CH2:16]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: COc1cc(C(=O)N2CCN(C(=O)/C=C(/C#Cc3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: COc1cc(C(=O)N2CCN(C(=O)/C=C(\C=C/c3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Reaction time: 15 h
Yield: 61 %

Procedure:
0.025 g of 10% w/w palladium-on-barium sulfate and two drops of quinoline were added to 5 ml of a methanol solution containing 0.250 g of 1-[(E)-3,5-diphenylpent-2-en-4-ynoyl]-4-(3,4,5-trimethoxybenzoyl)piperazine (prepared as described in Example 58). Hydrogen gas was introduced into the reaction mixture at room temperature and at atmospheric pressure. The reaction mixture was then shaken for 15 hours, after which the catalyst was filtered off and the solvent was removed by distillation under reduced pressure. The residue was subjected to moderate pressure liquid chromatography using a Lobar B column. 0.153 g of the title compound was obtained as a powder from those fractions eluted with mixtures of methylene chloride and ethyl acetate ranging from 3:2 to 1:3 by volume.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[O:17])[CH2:5]1)(=[O:3])[CH3:2].[CH:18](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6]([O:17][CH3:18])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: COC(OC)OC
Reactant: COC(=O)c1ccc2c(c1)N(C(C)=O)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1ccc2c(OC)cn(C(C)=O)c2c1

Procedure:
Methyl 1-acetyl-2,3-dihydroindol-3-one-6-carboxylate (233 mg, 1 mmol), trimethyl orthoformate (10 ml) and p-toluene sulphonic acid (20 mg) were heated under reflux for 3 h. in methanol (10 ml). The reaction mixture was concentrated under reduced pressure, poured into water and extracted with chloroform. After drying and evaporation, the product was purified by prep hplc;
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([CH3:12])=[C:10]([Br:13])[CH:9]=[C:8]([CH3:14])[N:7]=1)=[O:5])C.[NH2:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1>>[CH3:21][C:19]1[N:20]=[C:16]([NH:15][C:4]([C:6]2[C:11]([CH3:12])=[C:10]([Br:13])[CH:9]=[C:8]([CH3:14])[N:7]=2)=[O:5])[S:17][CH:18]=1
Reactant: CCOC(=O)c1nc(C)cc(Br)c1C
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)c2nc(C)cc(Br)c2C)n1

Procedure:
The title compound, white solid, MS (ISP): m/e=326.1, 328.0 (M+H)+, was prepared from 4-Bromo-3,6-dimethyl-pyridine-2-carboxylic acid ethyl ester and 2-Amino-4-methylthiazole in accordance with the general method of example 1, step 5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:7](=[O:21])[NH:6][C:5]2([CH2:26][N+:27]([O-])=O)[C:22]([F:25])([F:24])[F:23].[Cl-].[NH4+].O>CO.[Fe]>[NH2:27][CH2:26][C:5]1([C:22]([F:24])([F:25])[F:23])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:7](=[O:21])[NH:6]1
Reactant: COc1ccc(CN2C(=O)NC(C[N+](=O)[O-])(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1ccc(CN2C(=O)NC(CN)(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-1-(4-methoxybenzyl)-4-(nitromethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (1.0 g, 2.1 mmol), iron (294 mg, 5.3 mmol) and ammonium chloride (562 mg, 10.5 mmol) were stirred in methanol (5 mL) and water (5 mL) and the resulting solution was heated overnight under reflux. After the reaction solution was cooled to room temperature, methanol (10 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. After the resulting solid was removed by filtration, the mother liquid was concentrated, and the residue was washed sequentially with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure, whereby the objective compound (958 mg, quant.) was obtained as a colorless foamy solid.
Reaction SMILES: [C:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:5]=1[S:14]([NH2:17])(=[O:16])=[O:15])(=[O:3])[CH3:2].[H-].[Na+].I[CH3:21].Cl>CN(C)C=O>[CH3:21][NH:17][S:14]([C:5]1[C:6]([Cl:13])=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[C:1](=[O:3])[CH3:2])(=[O:15])=[O:16]
Reactant: CC(=O)c1c([N+](=O)[O-])ccc(Cl)c1S(N)(=O)=O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1C(C)=O
Temperature: 25 °C
Reaction time: 66 h
Yield: 62 %

Procedure:
To a mixture of 2-acetyl-6-chloro-3-nitrobenzenesulfonamide (300 mg, 1.02 mmol) and sodium hydride (53 mg, 1.32 mmol) in 10 mL of N,N-dimethylformamide, iodomethane (70 μL, 1.12 mmol) was added. The mixture was stirred at room temperature for 66 hours. The mixture was acidified with 1 N aq. HCl, then extracted with ethyl acetate. The solvent was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate/hexane/acetic acid (50/49/1, v/v/v), gave the desired product (185 mg, 59%). EI-MS (m/z) 307.3, 309.3 (M−).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:17][O:18][CH2:19][C:20]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:9]=1)(=O)[NH2:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]([CH2:17][O:18][CH2:19][C:20]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:9]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(N)=O)cc(-c3ccc(F)cc3)c2)(c2ccccc2)CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C#N)cc(-c3ccc(F)cc3)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred solution of tert-butyl 4-(((5-carbamoyl-4′-fluorobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (0.38 g, 0.72 mmol) in pyridine (6 mL) at 0° C. was treated with trifluoroacetic anhydride (1.0 mL, 7.2 mmol). The ice bath was removed and the reaction stirred at room temperature for 4 h. The reaction was cooled to 0° C. and quenched by the addition of excess methanol. The solvents were evaporated and the crude mixture dissolved in ethyl acetate and washed with 5% citric acid (2×), then water (2×), then brine (2×), dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (30% ethyl acetate/hexanes) to afford 0.3 g (83%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 7.65 (s, 1H), 7.41-7.44 (m, 3H), 7.34-7.36 (m, 4H), 7.22-7.24 (m, 2H), 7.13-7.17 (m, 2H), 4.41 (s, 2H), 3.75 (m, 2H), 3.44 (s, 2H), 2.01-3.06 (m, 2H), 2.19-2.22 (m, 2H), 1.83-1.88 (m, 2H), 1.43 (s, 9H). Mass spec.: 501.37 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]3[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][C:29]=4[F:34])[N:21]=3)[CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1>[F:34][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:28]=1[C:22]1[N:21]=[C:20]([N:16]2[CH2:17][CH2:18][O:19][C@@H:14]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])=[CH:9][CH:10]=3)[CH2:15]2)[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=1
Reactant: Cn1c(N2CCO[C@@H](c3ccc(N)cc3)C2)nc(-c2ccncc2F)cc1=O
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1ccc([C@H]2CN(c3nc(-c4ccncc4F)cc(=O)n3C)CCO2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 65.6 %

Procedure:
N,N-Dimethylcarbamoyl chloride (0.26 g, 2.41 mmol) was added to a solution of 2-((2S)-2-(4-aminophenyl)morpholine-4-yl)-3-methyl-6-(3-fluoropyridin-4-yl)-3H-pyrimidin-4-one (0.45 g, 1.18 mmol) and triethylamine (1.2 g, 11.9 mmol) in tetrahydrofuran (20 ml) and the solution was stirred at 50° C. for 48 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish N′-(4-((2S)-4-(6-(3-fluoropyridin-4-yl)-3-methyl-4-oxo-3H-pyrimidin-2-yl)morpholin-2-yl)phenyl)-N,N-dimethylurea (0.35 g, 67%) as white crystals.
Reaction SMILES: C(O[C:4]1(O[Si](C)(C)C)[CH2:6][CH2:5]1)C.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:4]1([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)[CH2:5][CH2:6]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(N2CCN(C3CC3)CC2)cc1
Temperature: 62.5 °C
Yield: 100 %

Procedure:
A mixture of [(1-ethoxycyclopropyl)oxy]trimethylsilane (4.5 mL. 22.4 mmol, 2 eq.), 1-(4-nitrophenyl)piperazine (2.32 g, 11.1 mmol, acetic acid (6.4 mL, 5 eq.), molecule sieves (3 A, 5 g), and sodium cyanoborohydride (2.1 g, 33.3 mmol, 3 eq.) in dry methanol (50 mL) is heated at 60-65° C. for 4 h. The reaction mixture is filtered, and the filtration is evaporated. The residue is dissolved in DCM (200 mL) and the resulting solution is washed with 2 N NaOH (100 mL), brine (100 mL×2), dried over MgSO4, and evaporated to provide a yellow solid (2.75 g, 100%). The compound is used in the next reaction without further purification. 1H NMR (300 MHz, DMSO-d6), δ 8.02 (d, J=9.6 Hz, 2H), 7.00 (d, J=9.6 Hz, 2H), 3.38-3.42 (m, 4H), 2.60-2.68 (m, 4H), 1.60-1.67 (m, 1H), 0.40-0.46 (m, 2H), 0.35-0.38 (m, 2H). LCMS-ESI (m/z): calcd for C13H17N3O2, 247.1; [M+H]+ found, 248.4.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:7][NH2:8])=[N:4][O:5][N:6]=1.C([N:17]=[C:18]=[S:19])(=O)C1C=CC=CC=1.N>CO>[CH3:1][C:2]1[C:3]([CH2:7][NH:8][C:18]([NH2:17])=[S:19])=[N:4][O:5][N:6]=1
Reactant: Cc1nonc1CN
Reactant: O=C(N=C=S)c1ccccc1
Agent: N
Solvent: CO
Product: Cc1nonc1CNC(N)=S
Yield: 78 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(a) by using 1-(4-methyl-1,2,5-oxadiazol-3-yl)methylamine (0.46 g, 4.1 mmol), benzoyl isothiocyanate (0.60 mL, 4.5 mmol) and ammonia in methanol (7 N, 25 mL) with the exception that the crude product isolated by filtration (0.55 g, 78% yield) was used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10]C)=[C:4]([O:12][CH3:13])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[OH:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[O:12][CH3:13]
Reactant: COc1cc(I)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(I)cc(OC)c1O
Temperature: 60 °C
Reaction time: 6 h
Yield: 69670 %

Procedure:
To a solution of 50.0 g of (0.170 mmol) of 1-iodo-3,4,5-trimethoxybenzene in methylene chloride (500 mL) was added 24.96 g (0.187 mmol) of aluminum chloride. The mixture was stirred at 60° C. for 6 hours. After cooling in an ice bath, ice (200 mL) and water (300 mL) were added and the resulting mixture was stirred. The reaction mixture was filtered through Celite and the aqueous layer of the filtrate was extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to yield crude crystals. The crude crystals were recrystallized from toluene-hexane, whereby 33.17 g of 4-hydroxy-l-iodo-3,5-dimethoxybenzene was obtained as a colorless crystalline powder (mp: 73.0 to 75.0° C., yield: 70%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:17]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[N:25][C:18]=3[N:19]([CH2:23][CH3:24])[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:14][CH:15]=1>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH:29]([C:26]1[CH:27]=[CH:28][C:17]2[C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=3)=[N:21][C:20](=[O:22])[N:19]([CH2:23][CH3:24])[C:18]=2[N:25]=1)[CH3:30]
Reactant: CCc1ccc2c(-c3cccc(Cl)c3)nc(=O)n(CC)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCn1c(=O)nc(-c2cccc(Cl)c2)c2ccc(C(C)Br)nc21
Temperature: 25 °C
Yield: 61.3 %

Procedure:
N-Bromosuccinimide (8.94 g, 50.2 mmol) and 200 mg of 2,2'-azobis(isobutyronitrile) were added to a solution of 15.0 g (47.8 mmol) of 4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one in 150 ml of carbon tetrachloride, followed by heating under reflux for 3 hours. The reaction solution was again mixed with 1.28 g (7.17 mmol) of N-bromosuccinimide and 100 mg of 2,2'-azobis(isobutyronitrile), followed by heating under reflux for 1 hour. After cooling to room temperature, insoluble matter was removed by filtration, and the resulting filtrate was mixed with water and extracted with carbon tetrachloride. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 11.5 g of 7-(1-bromoethyl)-4-(3-chlorophenyl)-1-ethylpyrido[2,3-d]pyrimidin-2(1H)-one in the form of crystals. The yield was 61%.