Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[NH:16][C:15]([CH3:22])([CH3:21])[CH:14]=[C:13]4[CH3:23])[C:10](=[O:24])[O:9][C:5]=2[CH:6]=[CH:7][CH:8]=1.CC(C[AlH]CC(C)C)C.CCOC(C)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl.CCCCCCC>[CH3:1][O:2][C:3]1[C:4]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[NH:16][C:15]([CH3:21])([CH3:22])[CH:14]=[C:13]4[CH3:23])[CH:10]([OH:24])[O:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc2oc(=O)c3c4c(ccc3c12)NC(C)(C)C=C4C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: COc1cccc2c1-c1ccc3c(c1C(O)O2)C(C)=CC(C)(C)N3
Temperature: 25 °C
Yield: 79.9 %

Procedure:
The product from Example 5 (75.2g, 98% potent, 0.23 mol) in CH2Cl2 (3.8 L) under N2 was cooled to −78° C. and treated with 1M DIBAL in heptane (328 ml) dropwise over 1-1.5 hours while maintaining the temperature below −76° C. The reaction was monitored by HPLC and/or TLC until the reaction was complete (1.5 hours). EtOAc (1 L) and a saturated Rochelle salt solution (2 L) was added. The mixture was allowed to warmed to room temperature and stirring was continued until the organic and aqueous layers clearly separated. The organic layer was then washed with brine (0.5L), dried over Na2SO4 and concentrated to a thick suspension (approx. 300 g). The suspension was then cooled to 0° C., filtered and washed with cold EtOAc. The wet cake was dried under reduced pressure at 40° C. to provide the title compound (59.4 g, 99% potent, 80% potency adjusted yield). A small reference sample was recrystallized from EtOAc. mp 184-5° C.; Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found C, 73.32; H, 6.51; N, 4.24. 1H NMR [(CD3)2SO] δ 1.08 (3H, s), 1.26 (3H, s), 2.23 (3H, s), 3.86 (3H, s), 5.42 (1H, s), 6.11 (1H, s), 6.56 (1H, d), 6.61 (1H, d), 6.64 (1H, d), 6,71 (1H, d), 6.94 (1H, d), 7.07 (1H, t), 7.99 (1H), d), 3C NMR [(CD3)2SO] δ 22.8, 28.1, 29.9, 49.6, 55.6, 89.8, 105.4, 110.8, 113.0, 113.9, 116.2, 117.0, 126.6, 127.2, 128.2, 130.0, 132.5, 145.4, 150.5, 156.5; FAB HRMS: calcd for C20H21NO3: 323.1521. Observed 323.1514.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[SH:13].[F:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Br>CN(C)C=O>[F:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH2:17][S:13][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[C:9]([Cl:10])[C:4]=1[Cl:3]
Reactant: COc1ccc(S)c(Cl)c1Cl
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(SCc2ccc(F)cc2F)c(Cl)c1Cl
Reaction time: 0.42 h

Procedure:
To a 1.26 g of sodium hydride in 25 ml dimethylformamide (sieve dried) is added dropwise a solution of 10 of 2,3-dichloro-4-methoxythiophenol in 25 ml dimethylformamide. After the addition is complete, the reaction mixture is stirred for 25 mins and a solution of 10 g of 2,4-difluorobenzyl bromide in 25 ml dimethylformamide is added dropwise. After this addition is complete, the mixture is stirred for 20 mins and cautiously poured onto ice-water. The aqueous mixture is extracted with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give an oil which crystallizes with cooling and trituration with hexane. Two recrystallizations with ethyl acetate-hexane give 5.1 g of (2,3-dichloro-4-methoxyphenyl) 2,4-difluorobenzyl sulfide, mp 86°-88°.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[C:11]([CH2:13][N:14]3[N:18]=[C:17]([NH2:19])[CH:16]=[N:15]3)[CH:10]=[CH:9][N:8]=2)[O:6]CCO1.[C:20]1([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[CH:12]=[C:11]([CH2:13][N:14]2[N:18]=[C:17]([NH:19][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:32])[CH:16]=[N:15]2)[CH:10]=[CH:9][N:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2cc(Cn3ncc(N)n3)ccn2)OCCO1
Product: CC(=O)c1cc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)ccn1

Procedure:
Following general procedure A followed by B, starting from 2-[2-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-4-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][C:8]1[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].Cl[CH2:25][C:26]([OH:28])=[O:27]>CN(C)C=O.O>[Cl:14][C:12]1[CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:21]=[CH:22][CH:23]=[C:2]([Cl:1])[CH:3]=2)[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH2:25][C:26]([OH:28])=[O:27])[CH2:17][CH2:16]2)=[N:10][CH:11]=1
Reactant: O=C(Nc1cc(Cl)cnc1N1CCNCC1)c1cccc(Cl)c1
Reactant: O=C(O)CCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CN1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
A mixture of 0.100 g (0.285 mmol) of 3-chloro-N-(5-chloro-2-piperazin-1-yl-pyridin-3-yl)-benzamide and 0.040 g (0.43 mmol) of chloroacetic acid in N,N-dimethylformamide is stirred overnight at room temperature then heated to 100° C. for 24 hours. The mixture is cooled to room temperature, diluted with water, and extracted with ethyl acetate. The aqueous phase is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC to provide 0.009 g (11%) of {4-[5-chloro-3-(3-chloro-benzoylamino)-pyridin-2-yl]-piperazin-1-yl}-acetic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:16])[F:17])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc(Oc3ccc(C#N)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 120 °C
Yield: 65.6 %

Procedure:
To a stirred solution of 5.0 g (0.017 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 150 mL of N,N-dimethylformamide was added 2.8 g (0.020 mole) of potassium carbonate. The resultant mixture was stirred for ten minutes, and 2.1 g (0.017 mole) of 4-fluorobenzonitrile was added. The mixture was stirred and heated at 120° C. for approximately 18 hours. The solvent was removed from the mixture by distillation under reduced pressure leaving a residue which was partitioned between diethyl ether and water. The organic phase was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give 4.4 g of 1-[4-chloro-5-(4-cyanophenoxy)-2-fluorophenyl]-4-difluoromethyl -4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:10][C:11]=1[F:12]>>[Cl:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[C:8]([C:13]([F:14])([F:15])[F:16])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1C(F)(F)F
Temperature: 40 °C
Reaction time: 5 h

Procedure:
About 500 parts of aqueous nitric acid was added slowly, with stirring, to a reaction vessel containing about 400 parts of 3-chloro-4-fluorobenzotrifluoride. The temperature of the reaction mixture was maintained at about 40° C. during the addition, then raised to about 60° C. and maintained thereat for about 5 hours. The reaction mixture was allowed to settle. The aqueous layer was removed and the organic layer was washed twice with 500 parts of water, treated several times with a saturated solution of sodium bicarbonate, washed with water again, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled at reduced pressure to yield 347 parts of 5-chloro-4-fluoro-2-nitrobenzotrifluoride.
Reaction SMILES: [C:1](NC1C(Cl)=CC(C(O)=O)=C(OC)C=1)(=O)[CH3:2].C(N(CC)CC)C.[NH2:24][C:25]1[C:41]([Cl:42])=[CH:40][C:28]([C:29]([NH:31][N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)=[O:30])=[C:27]([O:43][CH3:44])[CH:26]=1>CCOC(C)=O>[NH2:24][C:25]1[C:41]([Cl:42])=[CH:40][C:28]([C:29]([NH:31][N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:1][CH3:2])[CH2:34][CH2:33]2)=[O:30])=[C:27]([O:43][CH3:44])[CH:26]=1
Reactant: CCN1CCN(NC(=O)c2cc(Cl)c(N)cc2OC)CC1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCN1CCN(NC(=O)c2cc(Cl)c(N)cc2OC)CC1
Yield: 124.7 %

Procedure:
Reaction between 4-acetylamino-5-chloro-2-methoxy benzoic acid (3.2 g, 0.013 mole), triethylamine (1.3 g) and N-n-butyl-N'-amino piperazine (2.06 g) (prepared in similar manner to that described in Example 5) and hydrolysis as described in Example 1 gave 4-amino-5-chloro-2-methoxy-N-[4-n-butyl-1-piperazinyl]benzamide (2.80 g, 63%) as colourless microcrystals, m.p. 173.5°-174° C. (ex. EtOAc/light petrol 40°-60°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[N+:11]([O-])=O>C(O)C.C(O)(=O)C.[Fe].CCOC(C)=O>[Cl:17][C:15]1[CH:14]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:16]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11]
Reactant: O=[N+]([O-])c1nccn1Cc1cc(Cl)cc(Cl)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 80 °C
Yield: 90 %

Procedure:
1-(3,5-dichloro-benzyl)-2-nitro-1H-imidazole was dissolved in a mixture of ethanol and acetic acid, and Fe was added. The mixture was heated to 80° C. for 20 min. During this period of time, the mixture turned into reddish brown in color and then grayish white precipitate was formed. The reaction mixture was cooled to room temperature and diluted with EtOAc. The slurry was filtered through a pad of diatomaceous earth and washed with EtOAc. The filtrate was basified using 2N NaOH solution until pH ˜8. The organic phase was then separated and the aqueous layer was extracted with EtOAc. The combined EtOAc layer was dried over Na2SO4 and concentrated to afford 1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylamine as a white solid (80 mg, 90%).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:14]([OH:16])=O.[CH3:17][CH:18]([NH:20][C:21]1[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1)[CH3:19]>>[CH3:19][CH:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[N:27]1[CH2:28][CH2:29][N:30]([C:14]([C:2]2[NH:3][C:4]3[CH:5]=[CH:6][C:7]4[C:8]([C:9]=3[CH:1]=2)=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:16])[CH2:31][CH2:32]1)[CH3:17]
Reactant: O=C(O)c1cc2c(ccc3ccccc32)[nH]1
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3c(ccc4ccccc43)[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with benz[e]indole-2-carboxylic acid (PREPARATION 116, 0.5 g) and 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (PREPARATION 8, 0.52 g), the title compound is obtained, m.p. 228°-231°.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].Br[C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11].C(=O)(O)[O-].[Na+]>C1COCC1>[C:3]([CH:2]([C:1]#[N:5])[C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])#[N:4]
Reactant: N#CCC#N
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(C#N)C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In THF (91 ml), 3 g (45.411 mmol) of malononitrile were added slowly to 1.816 g (45.411 mmol) of sodium hydride (60% in mineral oil). Subsequently, 5.876 ml (45.411 mmol) of methyl 2-bromo-2-methylpropanoate were added and the mixture was stirred at RT overnight. Thereafter, another 5.876 ml (45.411 mmol) of methyl 2-bromo-2-methylpropanoate were added and the mixture was heated at 50° C. overnight. Then yet another 1.762 ml (13.623 mmol) of methyl 2-bromo-2-methylpropanoate were added and the mixture was heated at 50° C. for a further 4 h. Saturated aqueous sodium bicarbonate solution was then added to the reaction, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. This gave 8.9 g of crude product, which was purified by chromatography on silica gel (cyclohexane-ethyl acetate 4:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:16][C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][CH:25]([NH2:30])[CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH:20]=[CH:21][CH:22]=1>C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:30][CH:25]([CH:26]2[CH2:29][CH2:28][CH2:27]2)[CH2:24][CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[CH:18]=2)[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1nc(N)nc(Cl)n1
Reactant: Cc1cccc(CCC(N)C2CCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(CCC(Nc2nc(C)nc(N)n2)C2CCC2)c1

Procedure:
2.2 g (0.015 mol) of 2-amino-4-chloro-methyl-1,3,5-triazine and 4.1 g (0.03 mol) of K2CO3 are introduced into 50 ml of acetonitrile. 2.5 g (0.015 mol) of 3-(3-methylphenyl)-1-cyclobutyl-1-propylamine, dissolved in 20 ml of acetonitrile, are added dropwise to this solution. The mixture is then refluxed for 3 hours. The solid constituents are subsequently filtered off with suction and the filtrate is evaporated on a rotary evaporator. The residue is purified by means of column chromatography (eluant: ethyl acetate). This gives 4.3 g (92% of theory) of 2-amino-6-methyl-4-[3-(3-methylphenyl)-1-cyclobutyl-1-propylamino]-1,3,5-triazine.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC.[CH:21]([NH:23][C@@H:24]1[C:35](=[O:36])[N:26]2[C:27]([C:32]([OH:34])=[O:33])=[C:28]([CH3:31])[CH2:29][S:30][C@H:25]12)=[O:22]>O1CCCC1>[CH:21]([NH:23][C@@H:24]1[C:35](=[O:36])[N:26]2[C:27]([C:32]([O:34][CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:33])=[C:28]([CH3:31])[CH2:29][S:30][C@H:25]12)=[O:22]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reaction time: 8 h
Yield: 49.5 %

Procedure:
A solution of diphenyldiazomethane in ether (prepared from benzophenone hydrazone [21 g, 41.8 mmole]) was added to a solution of 7β-formamido-3-methylceph-3-em-4-carboxylic acid (9.7 g, 40.2 mmole) in tetrahydrofuran (150 ml) and the mixture was stirred overnight in the absence of light. The solvents were removed in vacuo and the residual oil was dissolved in methylene chloride (200 ml). The solution was washed with 3 %-sodium hydrogen carbonate solution (2 × 100 ml), dried, and evaporated to a yellow oil which was triturated with ethyl acetate-ether to give the title ester as a white crystalline solid (8.15 g, 49.5%), m.p. 136° to 140°, [α]D23 + 38° (c 0.94; Me2SO), λmax. (EtOH) 258 nm (ε 6,800), νmax. (Nujol) 3330 (NH), 1771 (azetidin-2-one), 1707 (CO2R) and 1655 and 1523 cm-1 (CONH), τ (Me2SO-d6) 1.91 (1H, d, J 9.5 Hz; NH), 1.89 (1H, s; CHO), 2.4 to 2.8 (10H, m; (C6H5)2CH), 3.07 (1H, s; (C6H5)2CH), 3.19 (1H,dd, J 9.5 and 5 Hz; C7 -H), 4.83 (1H,d, 5 Hz; C6 -H), 6.33 and 6.57 (2H, AB-q, 18 Hz; C2 -H2), 7.95 (3H, S; C3 -CH2) (Found: C, 64.55; H, 4.9; N, 6.7; S, 7.7. C22H20N2O4S (408.5) requires C, 64.7; H, 4.9; N, 6.9; S, 7.85%).
Reaction SMILES: [Na+].[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=O)=[O:14])=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.S(Cl)([Cl:19])=O.CN(C=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([Cl:19])(=[O:16])=[O:14])=[CH:9][CH:8]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)([O-])c1ccc(OCC2CC2)cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCC2CC2)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a suspention of 100 g (399.6 mmol) of 4-cyclopropylmethoxy-benzenesulfonic acid sodium salt, 186.55 ml (2557.5 mmol) of thionyl chloride and 6.19 ml (80 mmol) of DMF are added dropwise at r.t. After stirring for 15 h, the mixture is poured into ice water and extracted with CH2Cl2. The combined extracts are washed with H2O, dried over MgSO4 and concentrated under reduced pressure to give the title compound as a colorless solid; 1H-NMR (400 MHz, CDCl3): 0.35–0.45 (m, 2H), 0.65–0.75 (m, 2H), 1.25–1.35 (m, 1H), 3.91 (d, 2H, J=7.04 Hz), 7.02 (d, 2H, J=9.04 Hz), 7.96 (d, 2H, J=9.04 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH3:16][S:17][CH2:18][CH2:19][CH2:20][NH2:21].C(N(CC)CC)C>>[CH3:16][S:17][CH2:18][CH2:19][CH2:20][NH:21][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13]
Reactant: CSCCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: CSCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 83.8 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6- dichloro-3-nitrobenzenesulfonyl chloride (2 g, 6.88 mmol), 3-(methylthio)propylamine (0.72 g, 6.88 mmol) and triethylamine (1.92 mL, 13.76 mmol) were reacted to form the desired product (2.07 g, 82%). 1H NMR (MeOD-d4): δ 7.93 (d, 1H), 7.79 (d, 1H), 3.16 (t, 2H), 2.47 (t, 2H), 2.00 (s, 3H), 1.76 (m, 2H).
Reaction SMILES: [C:1]([CH2:5][S:6](Cl)(=[O:8])=[O:7])([F:4])([F:3])[F:2].[NH4+:10].[OH-]>C(Cl)Cl.O>[C:1]([CH2:5][S:6]([NH2:10])(=[O:8])=[O:7])([F:4])([F:3])[F:2]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)CC(F)(F)F
Temperature: 25 °C

Procedure:
The CF3CH2SO2NH2 was prepared by cooling a solution of commercially available CF3CH2SO2Cl (0.6 ml, 1 eq) in CH2Cl2 to 0° C. NH4OH (0.75 ml, 14.8 N, 2 eq) was then added dropwise. The mixture was allowed to warm to room temperature overnight. The reaction was diluted with water and extracted three times with CH2Cl2. The combined organic layers were dried with Na2SO4 and concentrated. The sulfonamide was used without further purification.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C:21](OCC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[BH4-]>C1COCC1>[CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH2:21][OH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of ethyl 5-benzyl-2-(2,5-difluorophenyl)oxazole-4-carboxylate (590 mg, 1.72 mmol) in THF (8.6 mL) was slowly added LiBH4 (56.2 mg, 2.58 mmol) at room temperature. The reaction mixture was stirred for overnight. After quenched with water, the reaction mixture was extracted with EtOAc. The organic layers was washed with saturated NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by automatic column chromatography (0 to 100% EtOAc in Hexanes) to yield (5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)methanol (460 mg, 88%) as a white solid. LC/MS (uplc): MH+ 302.2, 0.92 min.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[I-].[K+].CCN(C(C)C)C(C)C.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[N:23]=[C:22]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[O:32])[N:21]=1>CN(C=O)C>[F:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)=[N:21][C:22]([C:31]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[O:32])=[N:23]2)=[CH:28][CH:27]=1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccc(F)cc2n1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3cc(F)ccc23)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
A solution of 5-methyl-1H-pyrazol-3-amine (13 mg, 0.13 mmol), potassium iodide (15 mg, 0.088 mmol), and DIEA (0.016 mL, 0.088 mmol) in DMF (2 mL) was added to (4-chloro-7-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone (0.027 mg, 0.088 mmol). The resulting solution was stirred at rt overnight and then purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% HOAC/CH3CN and solvent A=0.05% HOAc/H2O) to give (7-fluoro-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone (10 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 6.48 (s, 1H), 7.36 (t, 2H), 7.60 (m, 2H), 8.09 (m, 2H), 8.29 (t, 1H), 10.78 (s, 1H), 12.23 (s, 1H); LC-MS (ESI) m/z 366 (M+H)+.
Reaction SMILES: CNCCNC.Br[C:8]1[C:9]([N+:25]([O-:27])=[O:26])=[C:10]([C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.[Cu]I>[CH3:21][C:20]([CH3:23])([CH3:22])[C:19]([NH:18][C:15]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([N+:25]([O-:27])=[O:26])[C:8]([N:28]2[CH2:32][CH2:31][CH2:30][C:29]2=[O:33])=[CH:17][CH:16]=1)=[O:24]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(Br)c1[N+](=O)[O-]
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(N2CCCC2=O)c1[N+](=O)[O-]
Temperature: 110 °C
Yield: 17.8 %

Procedure:
A solution of N,N′-dimethylethylenediamine (1.72 g) in toluene (15 mL) was added to a mixture of methyl 3-bromo-6-(2,2-dimethylpropionylamino)-2-nitro-benzoate (Intermediate 58, 1.72 g), pyrrolidin-2-one (0.489 g), copper(I) iodide (0.091 g) and potassium carbonate (1.32 g) and the mixture was stirred and heated under nitrogen at 110° C. for 5 hours. After cooling, the mixture was diluted with water and ethyl acetate and the organic phase was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-80% to give methyl 6-(2,2-dimethylpropionylamino)-2-nitro-3-(2-oxopyrrolidin-1-yl)-benzoate (0.310 g) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:18][C:19]1[N:20]=[CH:21][N:22]=[C:23]([O:17][C:4]2[CH:3]=[C:2]([CH3:1])[C:7]3[NH:8][C:9]([CH:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[N:10][C:6]=3[CH:5]=2)[CH:24]=1
Reactant: Cc1cc(O)cc2nc(C3CCOCC3)[nH]c12
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2nc(C3CCOCC3)[nH]c12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.35 g (0.84 mmol) 7-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-ol and 0.14 mg (0.90 mmol) 4,6-dichloropyrimidine were placed in 5.0 mL DMF. 0.35 g (2.52 mmol) potassium carbonate were added and the mixture was stirred overnight at 60° C. The reaction mixture was poured onto ice water, extracted with ethyl acetate and evaporated down i.vac. The residue was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase was dried and evaporated down i.vac.