Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:14]([CH3:13])(=[O:16])=[O:15])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(Br)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the reaction of 4-bromo-3-(trifluoromethyl)aniline with methanesulfonyl chloride as described in Example 45, Part A.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14][NH:15][CH3:16].Cl>O>[CH3:14][N:15]([CH3:16])[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CNC
Agent: Cl
Solvent: O
Product: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
30.0 g (148 mmol) of 5-chloro-2-nitrobenzoic acid was dissolved by stirring in 78 mL (744 mmol) of 50% dimethylamine aqueous solution under cooling in the ice bath. After the solution was put into a pressure-resistant container and sealed, the solution was stirred by heating in the oil bath for 23 hours at 60° C. The reaction solution was sufficiently cooled down and the inner pressure thereof was released. After confirming completion of the reaction by HPLC analysis, the reaction solution was put into another container (using 50 mL of water), 49.6 mL of concentrated hydrochloric acid, and then 200 mL of water were added thereto. Yellow crystals were precipitated by addition of hydrochloric acid. The crystallizing solution was matured at 10° C. overnight, separated by filtration and dried under reduced pressure to obtain 30.95 g of 5-dimethylamino-2-nitrobenzoic acid. (yield 99%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1>>[O:9]1[CH2:14][CH2:13][CH:12]([O:15][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11][CH2:10]1
Reactant: OC1CCOCC1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OC2CCOCC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and tetrahydropyran-4-ol by the method of Example 10 (b).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24]>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:24]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COC(=O)c1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NC(=O)c1ccc(OC)c(OC)c1
Reaction time: 0.5 h

Procedure:
Methyl 2-aminobenzoate (compound A) (2.0 g) was dissolved in anhydrous methylene chloride (40.0 ml). Subsequently, pyridine (2.0 ml) and 3,4-dimethoxybenzoyl chloride (compound B) (3.14 g) were added to the solution at room temperature, and the mixture was stirred at that temperature for 30 min. After the completion of the reaction, distilled water was added thereto, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, was dried over sodium sulfate, and was then concentrated to give methyl 2-[(3,4-dimethoxybenzoyl)amino]benzoate as a useful intermediate (4.17 g, yield 100%).
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:2]1.[CH3:15][N:16]([CH3:20])[C:17](=[S:19])[S-:18].C[NH2+]C>C(=S)=S>[CH3:15][N:16]([CH3:20])[C:17](=[S:18])[S:19][CH:6]([CH2:7][N+:8]([O-:10])=[O:9])[C:5]1[CH:11]=[CH:12][C:13]2[O:14][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccc2c(c1)OCO2

Procedure:
As in Example 17, reaction of 3,4-(methylenedioxy)-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave 3,4-(methylenedioxy)-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 122° C.- 124° C. when recrystallized without heating from acetone-ethanol solution.
Reaction SMILES: ClCC(N1CCN(C2C=CC=CC=2C)CC1)=O.[Cl:18][CH2:19][C:20](Cl)=[O:21].[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[Ca+2]>CN(C)C=O.C(C(C)=O)C>[Cl:18][CH2:19][C:20]([N:35]1[CH2:36][CH2:37][N:32]([C:25]2[C:26]([CH3:31])=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=2[CH3:23])[CH2:33][CH2:34]1)=[O:21]
Reactant: Cc1cc(C)c(N2CCNCC2)c(C)c1
Reactant: O=C(Cl)CCl
Agent: Cc1ccccc1N1CCN(C(=O)CCl)CC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: Cc1cc(C)c(N2CCN(C(=O)CCl)CC2)c(C)c1
Yield: 96 %

Procedure:
Compound 52A is prepared according to the procedure described for compound 12A, using the following reactants: chloroacetyl chloride (480 ml, 6.05 mmol); 1-(2,4,6-trimethylphenyl)piperazine (31A) (1.122 g, 5.5 mmol); calcium carbonate (1.65 g, 16.5 mmol); methyl ethyl ketone (25 ml) and dimethylformamide (10 ml) to solubilize the 1-(2,4,6-trimethylphenyl)piperazine).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 94.2 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 6.0 μL (0.0458 mMol) 2-methylbenzoyl chloride, 14.3 mg (95%) of the title compound were recovered.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Li]CCCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1>C1COCC1>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:21]1([OH:24])[CH2:22][CH2:23][C:18]2([O:25][CH2:15][CH2:16][O:17]2)[CH2:19][CH2:20]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: OCc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1ccccc1C1(O)CCC2(CC1)OCCO2
Temperature: -4 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromobenzyl alcohol (3.0 g, 16 mmol) in THF (40 mL) cooled at −78° C. was added a 2.5 M solution of n-BuLi in hexanes (14.1 mL). The mixture was stirred at −4° C. for 1 hour and cooled back to −78° C. To it was added a solution of 1,4-cyclohexanedione mono-ethylene ketal (2.5 g, 16 mmol) in TIE (10 mL) over 15 minutes. Stirring was continued at −78° C. for 30 minutes and at −4° C. for 1 hour. The reaction was quenched by addition of a solution of NH4Cl in water. The resulting solution was extracted with EtOAc three times. The combined extract was washed with brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 5% MeOH/CH2Cl2 provided the title compound. MS calculated (M+H)+265. Found 287 (M+Na)+.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[CH:4]([C:12](Cl)=[O:13])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC.C(Cl)Cl>[N+:1](=[CH:3][C:12]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:13])=[N-:2]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Product: [N-]=[N+]=CC(=O)C=Cc1ccccc1
Reaction time: 16 h

Procedure:
To a stirred solution of diazomethane (9.66 g, 0.23 mole) in dry ether (1250 ml.) maintained at 0° to -5°, was added a suspension of the styrene-carbonyl chloride polymer (10.0 g) from Example 7(c) in methylene chloride (50 ml.) over 15 minutes. Stirring was maintained for 5 hours at 0° to -5° and then for 16 hours at room temperature. The reaction mixture was filtered and the polymer washed with ether (2 × 100 ml.) and chloroform (2 × 100 ml.) and dried in vacuo at room temperature to constant weight. The title polymer (10.76 g) was deep yellow in colour and the IR spectrum exhibited absorptions at 2100 (diazo) and 1610 (carbonyl) cm-1. The composition of the polymer was confirmed by microanalysis.
Reaction SMILES: [C:1]1([P:7](Cl)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:18][CH2:17]1>C1COCC1>[C:1]1([P:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH2:28][CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH2:18][CH2:17]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Solvent: C1CCOC1
Product: O=C(CCc1cccnc1)NCCCCC1CCN(P(=O)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
3.4 ml (17.3 mmol) diphenylphosphinic acid chloride are dissolved in 100 ml absolute THF and cooled to ca. 0° C. under moisture exclusion. 5.0 g (17.3 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide and 4.8 ml (34.6 mmol) TEA are dissolved in 50 ml absolute THF and added dropwise under ice cooling. The mixture is stirred for three days at RT without further cooling. Subsequently, the solvent is removed under vacuum to a large extent and the residue is taken up in 100 ml 10% sodium hydroxide solution and extracted twice, each with 150 ml CHCl3. The combined organic phases are washed with saturated NaCl-solution, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (90/10) and crystallized from diisopropyl ether after drawing off the solvent. Colorless crystals with an MP of 134-135° C. yield 5.3 g (62%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH2:16][NH2:17])[C:10]=2[N:9]=[CH:8]1.CCN(C(C)C)C(C)C.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[NH:39][N:38]=[C:37]([CH:40]3[CH2:42][CH2:41]3)[CH:36]=2)[CH:31]=[CH:30][N:29]=1>CC(O)C>[CH:40]1([C:37]2[NH:38][N:39]=[C:35]([NH:34][C:32]3[CH:31]=[CH:30][N:29]=[C:28]([NH:17][CH2:16][C:15]4[C:10]5[N:9]=[CH:8][N:7]([CH:2]6[CH2:3][CH2:4][CH2:5][CH2:6][O:1]6)[C:11]=5[CH:12]=[CH:13][CH:14]=4)[N:33]=3)[CH:36]=2)[CH2:42][CH2:41]1
Reactant: NCc1cccc2c1ncn2C1CCCCO1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)c2ncn(C3CCCCO3)c2c1
Yield: 29.4 %

Procedure:
A mixture of 58 (200 mg, 0.87 mmol), DIPEA (335 mg, 2.61 mmol) and 53 (203 mg, 0.87 mmol) in IPA (3 mL) was irradiated in a microwave reactor at 120° C. for 2 h. The solvent was removed under reduced pressure to afford 110 mg (30%) of crude N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)methyl)pyrimidine-2,4-diamine (60) as brown solid, which was used in the step without further purification: MS (ESI) m/z=431.7 [M+1]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)=[N:2]1.ClCCl.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:17](=[O:18])[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8][CH:7]=2)=[N:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(-c2ccon2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccon2)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
4-Isoxazol-3-ylphenylamine (Intermediate 5, 4 g, 24.69 mmol) was added to dichloromethane (20 ml) followed by pyridine (4.6 ml). The solution was cooled to 0° C. and benzyl chloroformate (5.27 ml, 37.02 mmol) was added drop wise. The solution was allowed to stir for 2 hours at room temperature and then concentrated under vacuum. The residue was added to 30 ml of 1:1 hexane:EtOAc mixture. The crystals were collected by filtration to yield the product (2.26 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][N:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1
Reactant: CNC1CCN(C)CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(N(C)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
To a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (7.5 g, 36 mmol) in THF (180 mL) was added N,1-dimethylpiperidin-4-amine (5.5 g, 43 mmol) and NaHCO3 (6.0 g, 71 mmol). The mixture was stirred at RT and monitored by LCMS for disappearance of starting material. The reaction was filtered, concentrated, and partitioned between H2O and CH2Cl2. The aqueous layer was extracted several times with CH2Cl2, and the organics combined. The organics were washed with brine, dried with MgSO4, filtered, and concentrated to afford the desired product.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.C(=O)(O)[O-].[Na+].Cl[C:31]([O:33][CH3:34])=[O:32]>O1CCCC1.C(OCC)(=O)C>[CH3:34][O:33][C:31]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)=[O:32]
Reactant: COC(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N1CCC(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 150 mg) and sodium bicarbonate (75 mg) in dry tetrahydrofuran (6 mL) at 0° C. under N2 is treated with methyl chloroformate (38 μL), and the resulting mixture is stirred at 0° C. for one hour. The reaction is then diluted with ethyl acetate (20 mL), washed with water (10 mL) and saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue is recrystallized from methylene chloride/diethyl ether to give the title compound, mp 165-166° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Product: Brc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C

Procedure:
A mixture of 0.384 g (1.5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.774 g (4.5 mmol) 4-bromoaniline is heated under nitrogen atmosphere for 1.5 h at 90° C. The process is then carried out as in Example 21. Title compound is obtained after recrystallization from acetate/hexane and drying under HV (8 h at 100° C.); m.p. 201-202° C.; ESI-MS: (M+H)+=391 und 393.
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][C:10]3[CH:11]=[CH:12][N:13]4[C:19]([C:20]5[N:25]=[CH:24][CH:23]=[CH:22][N:21]=5)=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:34]>C(#N)C>[Cl:34][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][C:15]2[C:14]3=[N:17][N:18]=[C:19]([C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:13]3[CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccn3c(-c4ncccn4)nnc3c2cc1-c1ccccc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: Clc1nc2ccn3c(-c4ncccn4)nnc3c2cc1-c1ccccc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8(7H)-one (2-4) (1.4 g, 4.1 mmol) and DMF (0.032 mL) in acetonitrile (20 mL) was added POCl3 (2.3 mL, 24.6 mmol). After stirring at 120° C. for overnight, the solvent was removed under reduced pressure, and the residue was diluted with acetonitrile, and added water. The resulting solid was collected by filtration to give 8-chloro-9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine (2-5) as a colorless solid.
Reaction SMILES: O=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[N:20]1([CH:2]2[CH2:19][CH2:18][C:5]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:4][CH2:3]2)[CH2:23][CH2:22][CH2:21]1
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCC(N3CCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (stage (iv) Amine-F43) (1 g, 3.74 mmol) and azetidine (0.25 ml, 3.74 mmol) were placed in 1,2-dichloroethane (15 ml), and sodium triacetoxyborohydride (1.1 g, 5.23 mmol) was added. The reaction mixture was stirred for 3 d at room temperature, and then saturated sodium hydrogen carbonate solution was added. After phase separation, the aqueous phase was extracted with dichloromethane (2×). The combined organic phases were washed with saturated sodium chloride solution (1×), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol/ammonia (25% aq.), 100:10:1). Yield: 1 g (89%)
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10]C)=O.Cl.[Cl:13][CH:14]([CH3:18])[C:15](=[NH:17])[NH2:16].C(N(CC)CC)C>>[Cl:13][CH:14]([C:15]1[NH:17][C:8](=[O:10])[C:3]2[CH2:4][O:5][CH2:6][CH2:7][C:2]=2[N:16]=1)[CH3:18]
Reactant: COC(=O)C1COCCC1=O
Reactant: CC(Cl)C(=N)N
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(Cl)c1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 103.5 %

Procedure:
A mixture of methyl 4-oxotetrahydro-2H-pyran-3-carboxylate (1.0 g, 6.3 mmol), 2-chloropropanimidamide hydrochloride (0.9 g, 6.3 mmol), and triethylamine (3.52 mL, 25.4 mmol) was stirred at ambient temperature for 24 h. The mixture was concentrated in vacuo to give the title compound (1.4 g), which was used directly to the next step without further purification. MS m/z 215.2 (M+1), retention time=1.27 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3][CH2:2]1.Cl[C:16]1[C:17]2[C:24]([CH3:25])=[C:23]([C:26]([O:28][CH3:29])=[O:27])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[NH4+].O>O1CCOCC1>[CH3:25][C:24]1[C:17]2[C:16]([NH:14][C:13]3[C:8]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[N:9][CH:10]=[CH:11][CH:12]=3)=[N:21][CH:20]=[N:19][C:18]=2[S:22][C:23]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1cccnc1OC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OC3CCOCC3)c2c1C
Temperature: 25 °C
Yield: 47.2 %

Procedure:
2-(Tetrahydro-2H-pyran-4-yloxy)pyridin-3-amine (0.99 g, 5.10 mmol), methyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (1.237 g, 5.10 mmol) and para-toluene sulfonic acid (0.097 g, 0.51 mmol) were heated at reflux in anhydrous 1,4-dioxane (20 mL) for 16 hours. The solution was cooled to ambient temperature and poured into a stirred solution of ammonium hydroxide/water (1:4). The precipitate was filtered off, washed with water, diethyl ether and dried. The product was purified by reverse phase preparative HPLC to yield grey solid (0.963 g, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:9]([O:17][CH3:18])=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[CH:20](N)=[NH:21]>C(N)=O>[CH3:18][O:17][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH2:13][CH2:14][O:15][CH3:16])[N:1]=[CH:20][NH:21][C:4]2=[O:5]
Reactant: N=CN
Reactant: COCCOc1cc(N)c(C(=O)OC)cc1OC
Agent: Cl
Solvent: NC=O
Product: COCCOc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 140 °C
Yield: 73.6 %

Procedure:
According to the procedure described in Example 6A Step 4, a mixture of methyl 2-amino-5-methoxy-4-(2-methoxyethoxyl)benzoate (2.69 g, 10.5 mmol) and formamidine hydrochloride (1.208 g, 15 mmol) in formamide (10 mL) was heated at 140° C. for 8 hours, to afford 6-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one as a white solid (1.935 g, 74%). 1H NMR (300 MHz, DMSO-d6) δ 12.1 (br, 1H), 7.98 (s, 1H), 7.44 (s, 1H), 7.14 (s, 1H), 4.23 (t, 2H), 3.87 (s, 3H), 3.72 (t, 2H), 3.32 (s, 3H); LC-MS (ESI) m/z 251 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:5]([CH2:20][O:21]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:4]1>C(O)(=O)C.CC#N>[OH:21][CH2:20][C@@H:5]1[CH2:4][C@H:3]([O:2][CH3:1])[CH2:8][CH2:7][C@@H:6]1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CO[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: CC#N
Solvent: CC(=O)O
Product: CO[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
A sample of benzyl (1S,2R,4R)-4-methoxy-2-(trityloxymethyl)cyclohexylcarbamate (0.53 g) was dissolved in a mixture of 70% aqueous acetic acid (10 mL) and MeCN (10 mL) and stirred at 60° C. for 2 h. Reaction mixture was cooled and evaporated. Dissolved in EtOAc and washed with saturated NaHCO3 followed by brine and then dried (MgSO4). Filtered, concentrated and chromatographed to get benzyl (1S,2R,4R)-2-(hydroxylmethyl)-4-methoxycyclohexylcarbamate (0.24 g, yield=83%) as a clear oil. MS found: (M+H)+=294.29.
Reaction SMILES: [CH3:1][O:2][C:3](OC)(OC)[CH3:4].[NH2:9][C:10]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>>[CH3:1][O:2][C:3](=[N:9][C:10]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])[CH3:4]
Reactant: COC(C)(OC)OC
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Product: COC(=O)c1ccc(C(=O)OC)c(N=C(C)OC)c1

Procedure:
3.8 g (32 mmmol) of 1,1,1-trimethoxyethane and 1.5 g (7.17 nmuol) of dimethyl 2-aminoterephthalate are introduced into a reactor. The medium is stirred and refluxed for 5 h, and then concentrated to dryness at 50° C. under a vacuum of less than 1 mm Hg. 1.4 g of a thick brown oil are obtained.—TLC (99/1 CH2Cl2/MeOH): Rf=0.7 -0.8.