Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[F:11][CH:12]([F:25])[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH3:24])[C:15]=2[N:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH3:24])[C:15]=3[N:14]=[C:13]2[CH:12]([F:11])[F:25])[CH:7]=1
Reactant: CCOc1cccc2[nH]c(C(F)F)nc12
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cccc2c1nc(C(F)F)n2-c1cc(Cl)nc(SC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (700 mg), 2-(difluoromethyl)-4-ethoxy-1H-benzimidazole (761 mg), potassium carbonate (744 mg), and N,N-dimethylformamide (7 mL) was stirred at room temperature overnight. To the mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-80:20) to obtain 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-4-ethoxy-1H-benzimidazole (464 mg) (Preparation Example 86-1) and 1,1′-[2-(methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-4-ethoxy-1H-benzimidazole]. 1,1′-[2-(Methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-4-ethoxy-1H-benzimidazole] was suspended in ethyl acetate and warmed. After leaving to be cooled, the insoluble matter was collected by filtration to obtain 1,1′-[2-(methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-4-ethoxy-1H-benzimidazole] (275 mg) (Preparation Example 86-2).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[C:23]1[NH2:27]>>[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19][NH:27][C:23]3[NH:22][CH:26]=[CH:25][N:24]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: Nc1ncc[nH]1
Reactant: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CCl)cc1
Agent: Cl
Product: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CNc2ncc[nH]2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 1H-imidazol-2-amine. m/e+ 372 for C18H16Cl2N5 [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.27 (m, 4H), 6.92 (d, J=6.6 Hz, 2H), 6.76 (s, 2H), 4.67 (s, 2H), 4.50 (bs, 1H), 2.31 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=3[Cl:42])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1ccc(Sc2ccc(Br)cc2)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccc(Cl)cc3Cl)cc2)c1C
Yield: 28.8 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-2,4-dichlorobenzene (0.2 g, 0.61 mmol) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(2,4-dichloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.077 g, 29%) as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[CH:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>O.O1CCCC1>[CH3:14][N:13]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[N:2]([CH3:1])[CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCC=O
Reactant: CNc1cccc2cccc(NC)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC1N(C)c2cccc3cccc(c23)N1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of the N,N'-dimethyl-1,8-naphthalene diamine (0.50 g, 2.7 mmol, 186), tridecanal (0.56 g, 2.85 mmol. 197), p-toluenesulfonic acid (5 mg), and tetrahydrofuran (5 ml) was prepared and stirred at room temperature for 15 minutes. The mixture was basified with 25% sodium hydroxide (1.0 ml), diluted with water (20 ml) and extracted with ether (100 ml). The extract was dried over potassium carbonate, concentrated to give 2,3-dihydro-1,3-dimethyl-2-dodecyl perimidine as a solid: mp 30-32° C.; NMR (CDCl3) 7.13(m, 4H), 6.32(d, 2H), 4.27(t, 1H), 3.02(s, 6H), 1.7-1.1(m, 22H), 0.85(t, 3H); IR (neat) 1595 cm-1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([C:11]2[S:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)=[N:3]1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:16][C:14]3[S:15][C:11]([C:4]4[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:2]([CH3:1])[N:3]=4)=[CH:12][CH:13]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: Cn1nc(-c2ccc(C=O)s2)cc1C(F)(F)F
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4cc(C(F)(F)F)n(C)n4)s3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 491.1 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]4)=[O:21])=[CH:14][C:13]=3[C:33]([F:36])([F:35])[F:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:23][CH2:24][CH:25]([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]4)=[O:21])=[CH:14][C:13]=3[C:33]([F:35])([F:34])[F:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared by hydrolysis of the compound of Example 252 under basic conditions (aq. NaOH/EtOH), giving a white solid, mp 88° C. (dec.). 1H NMR (DMSO-d6, 300 MHz) δ 1.40 (m, 2H), 1.98 (m, 2H), 2.95 (m, 1H), 3.15 (m, 1H), 3.45 (m, 1H), 4.20 (m, 2H), 4.35 (m, 4H), 7.00 (m, 4H), 7.20 (m, 2H), 7.90 (m, 1H), 8.20 (m, 1H), 12.30 (s, 1H). MS (APCI) m/z 494 (M+H)+. Anal. calcd. for C24H22F3NO5S.0.1 H2O: C, 58.20; H, 4.52; N, 2.83. Found: C, 58.14; H, 4.69; N, 2.76.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:15][C:16]1[C:23]([F:24])=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[F:25]>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:15][C:16]1[C:23]([F:24])=[CH:22][C:19]([CH:20]2[O:12][CH2:11][CH:10]([CH:7]3[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:13][O:14]2)=[CH:18][C:17]=1[F:25]
Reactant: CCCC1CCC(C(CO)CO)CC1
Reactant: O=Cc1cc(F)c(Br)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCC1CCC(C2COC(c3cc(F)c(Br)c(F)c3)OC2)CC1
Yield: 60 %

Procedure:
6.0 g (0.03 mol) of 2-(4'-propylcyclohexyl)propane-1,3-diol, 6.6 g (0.03 mol) of 4-bromo-3,5-difluorobenzaldehyde and 0.3 g of TsOH were dissolved in 60 cm3 of dichloromethane, and it was refluxed for 3 hours on a hot water bath while removing the water produced with a Dean-Stark trap. After washing the reactant on water, the dichloromethane was removed. The residue was recrystallized from a solvent mixture of acetone and methanol to obtain 7.3 g (0.018 mol) of 2-(4'-bromo-3',5'-difluorophenyl)-5-(4'-propylcyclohexyl)-1,3-dioxane(trans-cis form mixture).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[C:23]([CH:28]=O)=[N:24][CH:25]=[CH:26][CH:27]=1>C(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=1)[CH2:28][C:23]1[C:22]([CH3:21])=[CH:27][CH:26]=[CH:25][N:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccnc1CNCCCCNC(=O)OC(C)(C)C
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1nccn1C

Procedure:
Using General Procedure B, reaction of {4-[(1-methyl-1H-imidazol-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester in CH2C2, 3-methyl-pyridine-2-carbaldehyde in CH2Cl2 and NaBH(OAc)3 gave {4-[(1-methyl-1H-imidazol-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a sticky white solid. 1H NMR (CDCl3) δ 1.43 (s, 9H), 2.01 (s, 3H), 2.05-2.08 (m, 4H), 2.30 (s, 3H), 2.64 (t, 1H, J=7.5 Hz), 2.94-3.04 (m, 2H), 3.56 (s, 2H), 3.82 (s, 2H), 4.20 (s, 2H), 6.81 (d, 1H, J=1.7 Hz), 7.09-7.15 (m, 2H), 7.43-7.45 (m, 1H), 8.40 (d, 1H, J=3.5 Hz). Deprotection with TFA using General Procedure F gave COMPOUND 230 as a white solid. 1H NMR (CDCl3) δ 1.22-1.32 (m, 2H), 1.41-1.49 (m, 4H), 2.21 (s, 3H), 2.48-2.55 (m, 4H), 3.41 (s, 3H), 3.64 (s, 2H), 3.72 (s, 2H), 6.76 (s, 1H), 6.87 (s, 1H), 7.06-7.10 (m, 1H), 7.40 (d, 1H, J=7.5 Hz), 8.35 (d, 1H, J=4.2 Hz). 13C NMR (CDCl3) δ 16.98, 22.56, 30.18, 31.41, 40.63, 49.44, 53.11, 57.94, 120.31, 121.43, 125.99, 131.96, 136.99, 144.58, 145.13, 155.90. ES-MS m/z 288 (M+H). Anal. Calcd. for C16H25N5.0.1H2O.0.2CH2Cl2.0.1CH4O: C, 63.28; H, 8.47; N, 22.64. Found: C, 63.59; H, 8.58; N, 22.30.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:12]=[C:11]([O:13][CH3:14])[C:10]3[O:15][C:16]4[C:21]([C@@:22]5([CH2:27][CH2:26][O:25][C:24]([NH2:28])=[N:23]5)[C:9]=3[CH:8]=2)=[CH:20][C:19]([NH2:29])=[CH:18][CH:17]=4)[CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:28][C:24]1[O:25][CH2:26][CH2:27][C@:22]2([C:9]3[CH:8]=[C:7]([C:4]4[CH2:3][CH2:2][O:1][CH2:6][CH:5]=4)[N:12]=[C:11]([O:13][CH3:14])[C:10]=3[O:15][C:16]3[C:21]2=[CH:20][C:19]([NH:29][C:37](=[O:38])[C:34]2[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][N:35]=2)=[CH:18][CH:17]=3)[N:23]=1
Reactant: COc1nc(C2=CCOCC2)cc2c1Oc1ccc(N)cc1[C@@]21CCOC(N)=N1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(C2=CCOCC2)cc2c1Oc1ccc(NC(=O)c3ccc(Cl)cn3)cc1[C@@]21CCOC(N)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
To a solution of (S)-3-(3,6-dihydro-2H-pyran-4-yl)-1-methoxy-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.080 g, 0.203 mmol) in THF/MeOH (20.3 mL) were added 5-chloro-2-pyridinecarboxylic acid (0.035 g, 0.223 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.066 g, 0.223 mmol). The resulting reaction mixture was stirred at RT for 2 h. The mixture was quenched with sat. NaHCO3 and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, concentrated, chromatographed on silica gel using 0-5% MeOH/DCM and repurified by HPLC to afford a white solid as (S)—N-(2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)-1-methoxy-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide (0.0401 g, 0.075 mmol, 37.0% yield).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:44])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]1[N:24]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[C:23](=[O:36])[C:22]([C:37]([O:39][CH3:40])=[O:38])=[C:21]([OH:41])[C:20]=1[CH2:42][CH3:43])=[CH:14][CH:13]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.[S:52](Cl)([C:55]1[CH:61]=[CH:60][C:58]([CH3:59])=[CH:57][CH:56]=1)(=[O:54])=[O:53]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:44])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]1[N:24]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[C:23](=[O:36])[C:22]([C:37]([O:39][CH3:40])=[O:38])=[C:21]([O:41][S:52]([C:55]3[CH:61]=[CH:60][C:58]([CH3:59])=[CH:57][CH:56]=3)(=[O:54])=[O:53])[C:20]=1[CH2:42][CH3:43])=[CH:14][CH:13]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCc1c(O)c(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CO[Si](C)(C)C(C)(C)C)n2C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1c(OS(=O)(=O)c2ccc(C)cc2)c(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CO[Si](C)(C)C(C)(C)C)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a stirred solution of methyl 6-(2-((tert-butyldimethylsilyloxy)methyl)-1-methyl-1H-indol-5-yl)-1-(2,4-dimethoxybenzyl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate (2.0 g, 3.2 mmol), prepared according to procedure described in Example 164, Step 2, in CH2Cl2 (15 mL) was added Et3N (0.68 mL, 4.9 mmol, 1.5 eq) and TsCl (0.74 g, 3.9 mmol, 1.2 eq) at 0° C. The mixture was allowed to warm to room temperature then stirred for 2 h. The solvent was removed and the residue was purified by flash column chromatography (0-25% EtOAc in CH2Cl2) to give the title compound (2.12 g, 85%). LC-MS 775.3 [M+H]+, RT 1.80 min.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[CH3:19][C:20]1([CH3:26])[NH:24][C:23](=O)[CH2:22][CH2:21]1.P(Cl)(Cl)(Cl)=O>>[CH3:19][C:20]1([CH3:26])[N:24]=[C:23]([N:6]2[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:22][CH2:21]1
Reactant: CC1(C)CCC(=O)N1
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1O2
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CCC(N2c3ccccc3Oc3ccc(C(F)(F)F)cc32)=N1

Procedure:
Reaction of 2-(trifluoromethyl)phenoxazine, 5,5-dimethyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE, m.p. 64°-67° C. Conversion of the free base to the hydrochloride salt affords 10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE HYDROCHLORIDE, m.p. 204.5°-207.5° C. (dec.) (corr.), in a 30% overall yield.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[O:25])=[N:13][CH:14]=1.[CH3:33][CH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=O.C([BH3-])#N.[Na+].Cl>>[ClH:8].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][N:29]([CH:35]3[CH2:36][CH2:37][CH2:38][CH:34]3[CH3:33])[CH2:28]2)=[O:25])=[N:13][CH:14]=1
Reactant: CC1CCCC1=O
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCC1N1CCC(OC(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)C1
Yield: 158.2 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(pyrrolidin-3-yloxycarbonyl)amino]benzamide trifluoroacetate (100 mg, 0.211 mmol), 2-methylcyclopentanone (0.112 mL, 1.05 mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded, after treatment with HCl, 80 mg (80%) of the title compound as the hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[Na+].Cl[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>O1CCCC1>[CH2:28]([O:27][CH2:26][N:3]1[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[C:2]1[CH3:1])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1[nH]c(-c2ccccc2)cc1C(=O)OCc1ccccc1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)OCc2ccccc2)cc(-c2ccccc2)n1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 500 mg portion of benzyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate was dissolved in 10 ml of tetrahydrofuran, and 79 mg of sodium hydride (55% dispersion in oil) was added under ice-cooling, followed by stirring at room temperature for 30 minutes. A 0.357 ml portion of benzyl chloromethyl ether was added dropwise to this solution under ice-cooling, followed by stirring at room temperature for 1.5 hours. After adding water under ice-cooling, extraction was carried out with ethyl acetate. Then, after washing with saturated brine and then drying with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10-1:8) to obtain 503 mg of benzyl 1-[(benzyloxy)methyl]-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate as a colorless liquid.
Reaction SMILES: [CH3:1]I.[H-].[Na+].[F:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][CH:18]3[NH:21][C:22]3[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=3)[O:25][CH2:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1>CN(C)C=O>[F:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][CH:18]3[N:21]([CH3:1])[C:22]3[CH:23]=[C:24]([CH:33]=[CH:34][CH:35]=3)[O:25][CH2:26][C:27]([O:29][CH:30]([CH3:31])[CH3:32])=[O:28])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)OC(=O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)COc1cccc(N(C)C2CCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
Methyl iodide (17 mg, 0.122 mmol) and sodium hydride (60% dispersion of mineral oil, 1.1 mg, 0.045 mmol) were added to a solution of isopropyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate (17 mg, 0.041 mmol) and dimethylformamide (2 mL) in a 50 mL round bottom flask at room temperature. The mixture was then heated to 50° C. and allowed to stir overnight. The solution was quenched with saturated ammonium chloride (25 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (1×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by preparative TLC (1000 mm thickness, 30% ethyl acetate/hexanes) to afford 12 mg (68%) of isopropyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)phenoxy)acetate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[C:36]5[O:35][CH:34]=[CH:33][C:32]=5[CH:31]=[CH:30][C:29]=4[Cl:37])=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:38][CH3:39])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:37][C:29]1[CH:30]=[CH:31][C:32]2[CH:33]=[CH:34][O:35][C:36]=2[C:28]=1[NH:27][C:21]1[C:20]2[C:25](=[CH:26][C:17]([O:16][CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[C:18]([O:38][CH3:39])[CH:19]=2)[N:24]=[CH:23][N:22]=1
Reactant: COc1cc2c(Nc3c(Cl)ccc4ccoc34)ncnc2cc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3c(Cl)ccc4ccoc34)ncnc2cc1OCCC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A mixture of 7-[2-(N-tert-butoxycarbonylpiperidin-4-yl)ethoxy]-4-(6-chlorobenzofuran-7-ylamino)-6-methoxyquinazoline (0.49 g), trifluoroacetic acid (4 ml) and methylene chloride (15 ml) was stirred at ambient temperature for 3 hours. The solvents were evaporated and the residue was diluted with toluene and evaporated again. The residue was partitioned between a mixture of methylene chloride and acetonitrile and a 2N aqueous sodium hydroxide solution. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The material so obtained was purified by column chromatography using increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution. The material so obtained was triturated under diethyl ether to give the title compound (0.296 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.4 (m, 2H), 1.75-1.95 (m, 5H), 2.9 (m, 2H), 3.3 (m, 2H), 4.05 (s, 3H), 4.3 (m, 2H), 7.15 (d, 1H), 7.4 (s, 1H), 7.55 (d, 1H), 7.8 (d, 1H), 8.1 (d, 1H), 8.2 (s, 1H), 8.8 (s, 1H), Mass Spectrum: M+H+ 453.
Reaction SMILES: [CH:1]([CH:4]([C:15]#[N:16])[C:5]1[CH:14]=[CH:13][C:10]([O:11][CH3:12])=[C:7]([O:8][CH3:9])[CH:6]=1)([CH3:3])[CH3:2].CO[CH2:19][CH2:20][C:21]#[N:22].C[O-].[Na+].O>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([C:4]([C:15]#[N:16])([CH:1]([CH3:3])[CH3:2])[CH2:19][CH2:20][C:21]#[N:22])[CH:14]=[CH:13][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C(C#N)C(C)C)cc1OC
Reactant: COCCC#N
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C#N)(CCC#N)C(C)C)cc1OC
Temperature: 85 °C

Procedure:
438.4 g (2 mol) of α-isopropyl-veratryl cyanide and 204.2 g (2.4 mol) of 3-methoxypropionitrile are dissolved in 400 ml of dimethylformamide, 36 ml of a 5.5 molar solution of sodium methylate are added, and the mixture is heated to 85° C. for 1/2 hour. After cooling, water is added to the reaction mixture and the reaction product separates by crystallisation. Recrystallised from methanol/water, the product melts at 97° C.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+]([O-])=O)([O-:11])=[O:10]>C(O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[C:13]([NH:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:14]=1
Reactant: NCC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NCC1CCCCC1
Reaction time: 2 h
Yield: 39.2 %

Procedure:
A solution of 13.6 g of cyclohexylmethylamine in 10 ml of 95° ethanol is added dropwise to a solution of 8.1 g of 1,2-dinitro-4-chlorobenzene in 20 ml of 95° ethanol. The temperature rises to 50° C. The reaction medium is stirred for 2 hours and the solvent is then evaporated off under vacuum. The residue is taken up with DCM, washed with water, then with 2N hydrochloric acid and then with water and dried over Na2SO4 and the solvent is then evaporated off under vacuum. The residue is chromatographed on silica using isopropyl ether as the eluent. 4.21 g of the expected product are obtained after recrystallization from heptane. M.p.=73° C.