Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[CH2:20]([NH:22][C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][NH:29][C:26]2=[N:27][CH:28]=1)[CH3:21].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:20]([N:22]([C:2]1[C:7]2=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9]([C:11]3[O:15][N:14]=[C:13]([CH3:16])[N:12]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1)[C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][NH:29][C:26]2=[N:27][CH:28]=1)[CH3:21]
Reactant: CCNc1cnc2[nH]ccc2c1
Reactant: Cc1noc(-c2cn3ncnc(Cl)c3c2C(C)C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(c1cnc2[nH]ccc2c1)c1ncnn2cc(-c3nc(C)no3)c(C(C)C)c12

Procedure:
The procedure described above in Example 24 was employed. Thus, when 4-chloro-5-isopropyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolo[2,1-f][1,2,4]triazine (86 mg, 0.31 mmol), ethyl-(1H-pyrrolo[2,3-b]pyridin-5-yl)-amine (50 mg, 0.31 mmol) and diisopropylethylamine (162 μL, 0.93 mmol) in DMF (2.0 mL) were used, the title compound was obtained. LCMS; m/z 403 (M+H)+. Monohydrochloride salt: 1H NMR (400 MHz, DMSO-d6) δ 9.70 (1H, s), 8.20 (1H, s.), 8.02 (1H, s), 7.52 (1H, s), 7.29 (1H, s), 6.38 (1H, br. s.), 4.10 (2H, q, J=6.8 Hz), 3.24(1H, m), 2.30 (3H, s), 1.19 (3H, t, J=6.8 Hz), 0.59 (6H, d, J=7.1 Hz). (1H, m), 2.30 (3H, s), 1.19 (3H, t, J=6.8 Hz), 0.59 (6H, d, J=7.1 Hz).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[OH-].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>>[CH2:18]([O:17][C:15]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reaction time: 1 h

Procedure:
trans-4-(Aminomethyl)cyclohexanecarboxylic acid (10.00 g, 0.06361 mol), in a 10% aq solution of NaOH (5.60 g in 55 mL) was cooled to 0° C. and treated over 15 min with vigorous stirring, with benzyl chloroformate (11 mL, 0.076 mol). After one hour the solution was acidified (1M HCl(aq)) and the resulting the white precipitate collected by filtration, washed with water and hexane then dried in vacuo oven overnight to afford 17.23 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 0.93-0.99 (m, 2H), 1.38-1.46 (m, 2H), 1.82-1.85 (m, 2H), 2.03-2.06 (m, 2H), 2.25 (m, 1H), 3.06 (t, J=5.6 Hz, 2H), 4.83 (m, 1H), 5.09 (s, 2H), 7.31-7.36 (m, 5H). MS (ES+): m/z 292 [MH+].
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][C:3]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([Cl:6])=[C:8]([C:14]([F:17])([F:15])[F:16])[CH:9]=1)=[O:4]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Chloroacetic acid chloride (0.69 ml; 8.44 mmol) is dropped slowly into a stirred solution of 4-chloro-3-trifluoro methyl aniline (1.5 g; 7.67 mmol) in pyridine (0.81 ml; 9.97 mmol) and dichloromethane (15 ml), cooled to 0° C. Stirring is continued for 2 h at room temperature. The reaction mixture is diluted with dichloromethane, washed twice with 1N aqueous hydrochloric acid and with water. The reaction mixture is then dried over Na2SO4, filtered and evaporated to yield 2.05 g (98%) brownish solid of 9.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[I-:12].[Na+]>CC(C)=O>[I:12][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1
Reactant: [I-]
Reactant: ClCCCOC1CCCCO1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCOC1CCCCO1
Yield: 93.3 %

Procedure:
2-(3′-Chloropropoxy) tetrahydro-2H-pyran (Aldrich) (9 g, 0.05 mol) was added to a solution of sodium iodide (37.8 g, 0.25 mol) in acetone (250 mL) with stirring. The resultant slurry was refluxed for 48 hours. The mixture was cooled, evaporated to a solid mass and transferred to the top of a short column of neutral alumina. The column was washed with CH2Cl2 (1 L) and CH2Cl2 was removed using a rotary evaporator. The product was obtained as yellow liquid (12.6 g, 93%). 1H NMR δ: 1.62-1.86 (m, 6 H, ring CH2), 2.07 (m, 2 H, CH2—CH2—I), 3.27 (m, 2 H, CH2—I), 3.38-3.54 (m, 2 H, CH2—O), 3.74-3.89 (m, 2 H ring O—CH2), 4.58 (t, 1 H, J=3.2 Hz, ring CH); λmax/nm (εmax/dm3 mol−1 cm−1) 267 (1500); HRMS (EI+) calc. for C8H15IO2: 269.0049. found 269.0039.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13](SC)=[N:14][CH:15]=3)[N:10]([CH2:20][CH3:21])[C:9]2=[O:22])=[CH:6][C:5]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:25])=[C:4]([F:37])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:49][NH2:50]>>[Cl:1][C:2]1[C:7]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13]([NH:50][CH3:49])=[N:14][CH:15]=3)[N:10]([CH2:20][CH3:21])[C:9]2=[O:22])=[CH:6][C:5]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:25])=[C:4]([F:37])[CH:3]=1
Reactant: CCN1C(=O)N(c2cc(NC(=O)Nc3cccc(C(F)(F)F)c3)c(F)cc2Cl)Cc2cnc(SC)nc21
Reactant: CN
Agent: O=C(OO)c1cccc(Cl)c1
Product: CCN1C(=O)N(c2cc(NC(=O)Nc3cccc(C(F)(F)F)c3)c(F)cc2Cl)Cc2cnc(NC)nc21
Yield: 88 %

Procedure:
Using a procedure analogous to Example A2, the sulfide was oxidized with mCPBA to the sulfone and then treated with methylamine to provide 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea (0.279 mmol, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.06 (s, 1H), 7.96 (brs, 1H), 7.87 (s, 1H), 7.64 (d, J=11 Hz, 1H), 7.50 (m, 2H), 7.33 (m, 1H), 7.02 (m, 1H), 4.60 (d, J=14 Hz, 1H), 4.40 (d, J=14 Hz, 1H), 3.95 (m, 2H), 2.78 (d, J=5 Hz, 3H), 1.15 (t, 3H); MS (ESI) m/z: 538.3 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:12](#[N:16])[CH2:13][C:14]#[N:15]>>[NH2:16][C:12]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:13]=1[C:14]#[N:15]
Reactant: N#CCC#N
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Product: N#Cc1c(-c2ccccc2)c[nH]c1N

Procedure:
18.3 g of 2-amino-3-cyano-4-phenylpyrrole (compound a), readily obtained by condensation of 2-aminoacetophenone hydrochloride and malononitrile in the presence of an alkali, and 25.3 g of ethoxyethylidene diethyl malonate were dispersed in 300 ml of ethanol, and 22.0 ml of a solution of 28% sodium methylate in methanol was added to the resulting dispersion, followed by heating under reflux for 5 hours. Thereafter, the reaction mixture was allowed to cool, and ethyl acetate was added thereto. After washing with water, the organic solvent was concentrated to precipitate crystals, which were then collected by filtration to obtain 11.6 g of compound b. Subsequently, 50 ml of fine oxocol and 2.0 g of titanium isopropoxide (Ti(O--i--Pr)4) were added to the compound b, and the resulting mixture was heated for 6 hours at an oil-bath temperature of 130° C. to 140° C. After being allowed to cool, the reaction mixture was purified by silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 14.7 g of coupler (III)-1 in the form of lemon yellow oily matter.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].Cl[C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH3:19])[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][N:12]=1>C(N(CC)C(C)C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH3:19])[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][N:12]=1
Reactant: Oc1c(F)cccc1F
Reactant: CCNc1nc(Cl)ncc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc(Oc2c(F)cccc2F)ncc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 73 %

Procedure:
2,6-Difluorophenol (2.1 g, 16.1 mmol) is added to a solution of (2-chloro-5-nitro-pyrimidin-4-yl)-ethyl-amine, 6, (3.0 g, 14.9 mmol) in N,N-diisopropyl ethylamine (50 mL). The reaction is heated to reflux (˜130° C.) under N2 for 3 hours at which point monitoring of the reaction via LC/MS indicates the starting material is consumed. The mixture is diluted with 1 N HCl (500 mL) and the resulting mixture extracted three times with EtOAc (500 mL). The organic layers are combined, dried over MgSO4 and concentrated in vacuo to an oil which is purified over silica (15% EtOAc/hexane) to afford 3.2 g (73% yield) of the desired product as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 8.43 (br s, 1H), 7.13-7.23 (m, 1H), 6.98 (t, J=7.8 Hz, 2H), 3.44-3.53 (m, 2H), 1.22 (t, J=7.2 Hz, 3H); ESI/MS: 297 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[C:9]([CH3:12])[N:10]=2)[N:5]([C@@H:14]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[CH2:15]2)[C:4](=[O:22])[N:3]=1.[Cl-].C[N+]1C=CN([C:30]([O:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:31])C=1.O>CN(C=O)C>[CH3:12][C:9]1[N:10]=[C:11]2[C:6](=[N:7][C:8]=1[CH3:13])[N:5]([C@@H:14]1[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[CH2:15]1)[C:4](=[O:22])[N:3]=[C:2]2[NH:1][C:30]([O:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:31]
Reactant: Cc1nc2c(N)nc(=O)n([C@H]3C[C@H](O)[C@@H](CO)O3)c2nc1C
Reactant: C[n+]1ccn(C(=O)OCCc2ccc([N+](=O)[O-])cc2)c1
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(NC(=O)OCCc3ccc([N+](=O)[O-])cc3)nc(=O)n([C@H]3C[C@H](O)[C@@H](CO)O3)c2nc1C
Temperature: 25 °C

Procedure:
A mixture of 1.54 g (5 mmol) of 4-amino-6,7-dimethyl-1-(2-deoxy-β-D-ribofuranosyl)-pteridine-2-one (56) and 1.87 g (6 mmol) of 1-methyl-3-[2(4-nitrophenyl)ethoxycarbonyl]imidazolium chloride (see Himmelsbach, et al. Tetrahedron 40: 59 (1984) which is herein incorporated by reference) in 80 mL of anhydrous DMF was stirred at room temperature over night. To this solution was slowly added 100 mL of H2O with stirring. The solution was then cooled and the precipitate collected by suction and, after washing with methanol and ether and drying in a desiccator, gave 57 as 2.0 g (80% yield) of crude material. Recrystallization from methanol yielded 1.5 g (60% yield) of colorless crystals (m.p. 154°-155° C.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH-:9])(=[O:8])=[O:7].C(Cl)(=O)[C:11](Cl)=[O:12]>ClCCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]=[C:11]=[O:12])(=[O:8])=[O:7]
Reactant: [NH-]S(=O)(=O)c1cccs1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NS(=O)(=O)c1cccs1

Procedure:
A mixture of 2-thiophenesulfonylamide (1.5 g) and oxalyl chloride (6 mL) in 10 mL of 1,2-dichloroethane was refluxed for 14 h. The solvent was removed under vacuum and the crude used as is for the next step.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([CH3:14])[NH:11][C:12]=1[CH3:13])C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:14][C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[C:12]([CH3:13])[N:11]=1
Reactant: CCOC(=O)NN=Cc1nc(C)[nH]c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(C)n2c(=O)[nH]ncc12

Procedure:
A mixture of 7.37 gm. of 3-[(2,5-dimethyl-4-imidazoly)methylene]carbazic acid ethyl ester and 50 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product, m.p. 263°-263.5° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=1.[C:18](=[O:20])=[O:19]>C1COCC1>[CH2:14]([S:13][C:10]1[CH:11]=[CH:12][C:7]([C:18]([OH:20])=[O:19])=[CH:8][CH:9]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCSc1ccc(Br)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCSc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
n-Butyllithium (6.8 ml, 10.0M in hexane, 0.068 mol) was added to a stirred, cooled (-78° C.) solution of compound 1 (16.56 g, 0.067 mol) in dry THF (200 ml), under dry nitrogen at -78° C. The mixture was maintained under these conditions for a further 0.5 h (glc analysis confirmed a complete reaction) before being poured into a slurry of `Cardice` and dry THF. The mixture was allowed to warm to room temperature overnight. The combined organic extracts were evaporated in vacuo and the residue was dissolved in boiling acetic acid. Ice (400 g) was added to the solution and the product was filtered off and dried in vacuo (KOH, P2O5).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:31](=[O:39])(=[O:38])[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=1>C(#N)C>[C:8]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:31](=[O:39])(=[O:38])[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=S1(=O)c2ccccc2N(c2ccc(O)cc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Oc1ccc(N2c3ccccc3S(=O)(=O)c3ccccc32)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
0.68 g (6.68 mmol) of triethylamine and 0.34 g (2.44 mmol) of benzoyl chloride were added to a solution of 0.72 g (2.22 mmol) of 10-(4-hydroxyphenyl)phenothiazine 5,5-dioxide in 120 ml of acetonitrile. After stirring at room temperature for 45 min, the solvent was distilled off. The residue was taken up in 100 ml of hot water and stirred at 75° C. for 30 min. The solid was filtered off with suction while hot, washed with hot water and dried at 120° C. in a forced-air drying cabinet. 0.87 g (92% of theory) of colorless microcrystals having an m.p. of 233-235° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[NH:16][C:17](=[O:20])[CH2:18][O:19][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].[CH2:30](Br)[C:31]#[CH:32]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[N:16]([CH2:32][C:31]#[CH:30])[C:17](=[O:20])[CH2:18][O:19][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: C#CCBr
Reactant: Cn1nc(-c2cc3c(cc2F)NC(=O)CO3)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C#CCN1C(=O)COc2cc(-c3nn(C)c(C(F)(F)F)c3Cl)c(F)cc21
Temperature: 45 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
At 25° C., 2.7g (7.7 mmole) the product of step A, 1.1g (8.0 mmole) K2CO3 and 0.9 mL (8.0 mmole) 80% propargyl bromide were slurried in 25 mL DMSO. The mixture was stirred at 45° C. for 16 hours. The mixture was cooled, diluted with 100 mL cold water and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4 and stripped in vacuo. The residue was purified chromatographically using methylene chloride as the eluent to give 2.7 g (90%) of 7-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-6-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one as a white solid, mp 184° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:16])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5].[C:27]([O:31][C:32]([NH:34][CH:35]([C:46]([NH:48][C@@H:49]([C:51](OC)=[O:52])[CH3:50])=[O:47])[CH2:36][C:37]1[C:42]([CH3:43])=[CH:41][C:40]([OH:44])=[CH:39][C:38]=1[CH3:45])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([NH:34][C@H:35]([C:46]([NH:48][C@@H:49]([C:51]([NH:2][CH2:3][C:4]([NH:6][C@H:7]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:16])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])=[O:52])[CH3:50])=[O:47])[CH2:36][C:37]1[C:42]([CH3:43])=[CH:41][C:40]([OH:44])=[CH:39][C:38]=1[CH3:45])=[O:33])([CH3:28])([CH3:29])[CH3:30]
Reactant: COC(=O)[C@@H](C)NC(=O)C(Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C
Reactant: COC(=O)CCCCCNC(=O)[C@H](CC1CCCCC1)NC(=O)CN
Agent: Cl
Product: COC(=O)CCCCCNC(=O)[C@H](CC1CCCCC1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C

Procedure:
The title compound is prepared by the method of Example 1 from the title product of Example 121 and the fast diastereomer (D) of Example 114.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[C:12]#[N:13]>C1COCC1>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:4][CH2:3][C:2]([NH2:1])([CH3:6])[CH3:5])[C:11]=1[C:12]#[N:13]
Reactant: CC(C)(N)CO
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(N)COc1cccc(N)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of 2-amino-2-methylpropan-1-ol (14.4 g, 161 mmol) in anhydrous THF (150 mL) was added NaH (6.8 g, 161 mmol, 60% in mineral oil) in small portions at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 minutes and then stirred at room temperature for another 30 minutes. The solution was cooled down to 0° C. again, and to this solution was added dropwise a solution of 2-amino-6-fluorobenzonitrile (20.0 g, 147 mmol) in anhydrous THF (50 mL). The reaction mixture was then refluxed overnight under nitrogen. The reaction mixture was cooled down to room temperature and carefully quenched with aqueous NH4Cl solution and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by chromatography on silica gel eluting with 10% MeOH in DCM to give the title compound as yellow solid (23.4 g 71%). 1H NMR (400 MHz, DMSO-d6) δ 1.08 (s, 6H), 3.15 (s, 2H), 3.64 (s, 2H), 5.98 (s, 2H), 6.13 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 7.15 (t, J=8.4 Hz, 1H). MS 236 (MH+).
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>C(O)(=O)C>[CH3:1][C:2]1[N:15]([C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[Cl:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1ccccc1Cl
Reactant: Cc1nc2ccsc2c(=O)o1
Solvent: CC(=O)O
Product: Cc1nc2ccsc2c(=O)n1-c1ccccc1Cl
Yield: 51.3 %

Procedure:
2-Methyl-thieno[3,2-d][1,3]oxazin-4-one (1.67 g, 10 mmol) and o-chloroaniline (2.1 mL, 20 mmol) were combined in acetic acid (20 mL) and refluxed for 4.5 hours. The reaction was partitioned between ethyl acetate and water. The two phase mixture was treated with sodium bicarbonate until the aqueous layer was basic and the phases were then separated. The aqueous phase was extracted with ethyl acetate and the combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated to leave a brown oil. This residue was purified by flash chromatography on silica gel (30×150 mm). Elution with 10% and 20% ethyl acetate/hexane gave 1.42 g (51%) of 2-methyl-3-(2-chlorophenyl)-3H-thieno[3,2-d]pyrimidin-4-one was isolated as a brown oil which solidified on standing.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)=[C:8]([F:33])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:32]2[CH:31]=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)[C:8]([F:33])=[CH:7][C:6]=2[N:5]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3F)c2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3cc4sc(N)nc4cc3F)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
Potassium thiocyanate (500 mg, 5.12 mmol) was suspended in acetic acid (10 mL) and the mixture was stirred at room temperature for 10 min. To the obtained solution was added a solution of N-[3-(4-amino-2-fluorophenoxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide (500 mg, 1.28 mmol) in acetic acid (10 mL), and the mixture was further stirred at room temperature for 15 min. To the obtained solution was added dropwise slowly a solution of bromine (0.225 g, 1.41 mmol) in acetic acid (7.0 mL) and, after the completion of the dropwise addition, the mixture was stirred at room temperature for 14 hr. The resulting yellow insoluble material was filtrated, and washed with acetic acid. The filtrate and washing were combined and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (300 mL), washed with 5% aqueous sodium hydrogencarbonate solution (200 mL×2), water (200 mL) and saturated brine (200 ml), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (0.32 g, 57%) as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[O:11][C:12](=[O:14])[CH3:13].[Br:15]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[O:11][C:12](=[O:14])[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1c(C)sc2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(=O)Oc1c(CBr)sc2ccccc12
Yield: 102.7 %

Procedure:
A suspension of 1.00 g (4.85 mmol) of 2-methyl-3-acetoxybenzo[b]thiophene, 1.21 g (6.78 mmol) of N-bromosuccinimide, and 10 mg benzoylperoxide was heated under reflux for 3 hours. The mixture was filtered and the filtrate was concentrated to afford 1.42 g (100%) of a pale yellow oil. NMR (CDCl3, 90 MHz) δ2.35 (s, 3H, OAc), 4.48 (s, 2H, --CH2 --Br), 7.2-7.8 (m, 4H).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([CH3:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:35]([C:34]3[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:33]=3[Cl:32])[OH:36])=[N:3][CH:4]=[C:5]([CH3:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1C(O)c1cc([N+](=O)[O-])ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (472 mg, 1.0 mmol) in THF (3 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 1.2 mL, 2.4 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 2-chloro-5-nitro-benzaldehyde (352.6 mg, 1.9 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). Combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. Obtained residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-{2-[(2-chloro-5-nitro-phenyl)-hydroxy-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (441 mg) in 76% yield. ESMS m/z (relative intensity): 580 (M+H)+ (100), 602 (M+Na)+ (20).