Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[O:8][CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][O:28][CH3:29])[CH2:10][CH:11]2[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH:14]=[CH:13][CH2:12]2)=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.P([O-])([O-])([O-])=O>[OH:8][CH:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][O:28][CH3:29])[CH2:10][CH:11]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH:14]=[CH:13][CH2:12]1
Reactant: COCOc1ccccc1C(CC1CC=CC(=O)CCC1)OCc1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: COCOc1ccccc1C(O)CC1CC=CC(=O)CCC1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
84 mg of the compound obtained in Example 29 was dissolved in a mixed solvent of 5 ml of dichloromethane and 5 ml of phosphate buffer (pH 6.8). To the resulting solution was added 0.10 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The solution was stirred at room temperature for three and a half hours. The reaction solution was diluted with dichloromethane, washed with a saturated sodium bicarbonate aqueous solution, and dried over anhydrous sodium sulfate. Then, the solvent was evaporated. The residue was purified on silica gel column, and the eluate with ethyl acetate-hexane (1:4) was collected, to afford 49 mg of the titled compound as colorless liquid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:26])[C:14]3[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:32])[CH:8]=[CH:7][C:6]1=2.[CH3:33][C@H:34]1[CH2:39][NH:38][CH2:37][C@@H:36]([CH3:40])[NH:35]1>>[Cl:26][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([O:24][CH3:25])[C:18]=1[C:15]1[C:14]2[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:13]=2[C:12]2[C:11]3[CH:10]=[C:9]([OH:32])[CH:8]=[CH:7][C:6]=3[N:5]([CH2:4][CH2:3][CH2:2][N:38]3[CH2:37][C@H:36]([CH3:40])[NH:35][C@H:34]([CH3:33])[CH2:39]3)[C:17]=2[CH:16]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCCBr
Product: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCCN1C[C@@H](C)N[C@@H](C)C1
Reaction time: 20 h
Yield: 98 %

Procedure:
Bromide (207) (60 mg, 0.12 mmol), prepared as described in example 176, was reacted with cis-2,6-dimethylpiperazine according to the procedure described in example 179 except that the reaction was performed at room temperature for 20 h, to give amine (218) (63 mg, 98%) as a yellow powder, mp 199–202° C. 1H NMR δ [(CD3)2SO] 10.99 (br s, 1H), 9.37 (br s, 1H), 8.36 (d, J=2.4 Hz, 1H), 7.75 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.43 (t, J=8.2 Hz, 1H), 7.15 (m, 3H), 4.45 (t, J=6.1 Hz, 2H), 3.67 (s, 3H), 2.49 (m, 4H), 2.11 (m, 2H), 1.90 (m, 2H), 1.27 (m, 2H), 0.79 (m, 6H). Found: C, 61.35; H, 5.68; N, 9.14. C30H31ClN4O4.2¼H2O requires: C, 61.32; H, 6.09; N, 9.54.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:3]([O:13][CH3:14])[C:4]=1[N+:10]([O-:12])=[O:11])=[O:7]
Reactant: COC(=O)CBr
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C=O)c([N+](=O)[O-])c1OC
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
A solution of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde (2.0 g, 10 mmol) in DMF (10 mL) was added with methyl bromoacetate (1.1 mL, 11 mmol) and potassium carbonate (2.1 g, 15 mmol), followed by stirring for 1.5 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain methyl (4-formyl-2-methoxy-3-nitrophenoxy)acetate (2.2 g, 84%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH3:31][O:32][CH2:33][C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:35]4[C@H:34]([CH2:33][O:32][CH3:31])[CH2:38][O:37][C:36]4=[O:39])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: COC[C@@H]1COC(=O)N1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(N2CCCS2(=O)=O)c1
Yield: 71.4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 118 and (R)-4-methoxymethyloxazolidin-2-one (65.6 mg) described in Preparation Example 38, the title compound (194.2 mg) was obtained.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1([F:62])[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][N:56]=3)=[CH:51][CH:50]=2)([C:36]([NH:38][CH2:39][CH:40]([OH:47])[CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][CH3:44])=[O:37])[CH2:25]1>ClCCl>[CH3:45][C:42]([CH3:46])([CH2:43][CH3:44])[CH2:41][C:40](=[O:47])[CH2:39][NH:38][C:36]([C:26]1([CH2:48][C:49]2[CH:50]=[CH:51][C:52]([C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][N:56]=3)=[CH:53][CH:54]=2)[CH2:25][C:24]([F:62])([F:23])[CH2:28][N:27]1[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[O:37]
Reactant: CCC(C)(C)CC(O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(C)(C)CC(=O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CC(F)(F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (304 mg, 0.72 mmol) was added to an ambient temperature solution of tert-butyl 4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]-2-{[(2-hydroxy-4,4-dimethylhexyl)amino]carbonyl}pyrrolidine-1-carboxylate (202 mg, 0.36 mmol) in dichloromethane (5 mL). After stirring at ambient temperature for 1 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate (1:1) and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded tert-butyl 2-{[(4,4-dimethyl-2-oxohexyl)amino]carbonyl}-4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=O>>[Cl:27][C:25]1[CH:26]=[C:18]2[C:19]([C:20](=[O:22])[N:14]([S:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:13])=[O:12])[C:15](=[O:16])[NH:17]2)=[CH:23][CH:24]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: COc1ccc(S(=O)(=O)N=C=O)cc1OC
Product: COc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1OC
Yield: 35 %

Procedure:
897 mg (3.69 mmol) of 3,4-dimethoxybenzenesulfonylisocyanate and 633 mg (3.69 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 512 mg of the above-identified compound (yield 35.0%). Properties: colorless crystal, Melting point: >250° C., PMR (δppm, DMSO-d6): 3.85 (3H,s), 3.88 (3H,s), 7.12 (1H,s), 7.22 (2H,d), 7.67 (1H,s), 7.77 (1H,d), 7.86 (1H,d), 11.63 (1H,br).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[C:4]([C:17]2[CH:18]=[N:19][C:20](S(CCC)(=O)=O)=[N:21][CH:22]=2)[CH:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:17]2[CH:22]=[N:21][C:20]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:19][CH:18]=2)[CH:3]=1
Reactant: C1COCCN1
Reactant: CCCS(=O)(=O)c1ncc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cn1
Product: O=C(O)COc1ccc(Cl)cc1-c1cnc(N2CCOCC2)nc1

Procedure:
The title compound was prepared from the product of example 20 step (iv) and morpholine by the method of example 20 step (v).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C@H:27]1([NH2:34])[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1>CS(C)=O>[NH2:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([NH:34][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:29]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cccc(CNc2cc(C(F)(F)F)cc(-c3ccnc(F)c3)n2)c1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3cc(C(F)(F)F)cc(NCc4cccc(F)c4)n3)ccn2)CC1
Temperature: 105 °C

Procedure:
To 2′-fluoro-N-(3-fluorobenzyl)-4-(trifluoromethyl)-2,4′-bipyridin-6-amine (34 mg, 0.093 mmol) was added DMSO (1.7 ml) and trans-cyclohexane-1,4-diamine (159 mg, 1.396 mmol). The resulting reaction mixture was stirred at 105° C. until completion as indicated by LCMS, about 40 hours. To the crude reaction mixture was added 0.75 ml of DMSO, filtered and purified by prep LC. After lyphilization, 28.1 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 460.3 (MH+), retention time=0.72 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.40-1.72 (m, 4H) 2.18 (t, J=13.77 Hz, 4H) 3.11-3.24 (m, 1H) 3.62-3.76 (m, 1H) 4.72 (s, 2H) 6.95 (s, 1H) 7.12 (d, J=9.96 Hz, 1H) 7.17-7.24 (m, 1H) 7.27-7.37 (m, 1H) 7.40 (s, 1H) 7.42-7.48 (m, 1H) 7.69 (s, 1H) 7.87 (d, J=6.74 Hz, 1H)
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:9][OH:10])[C:5]([F:8])=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25](Cl)=[O:26])[C@H:21]([CH2:28][CH3:29])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[C:3]([F:11])=[C:4]([C:5]([F:8])=[CH:6][CH:7]=1)[CH2:9][O:10][C:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:18])[CH2:20][C@H:21]1[CH2:28][CH3:29])=[O:26]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: OCc1c(F)ccc(Br)c1F
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(Br)c1F

Procedure:
The compound was prepared from (3-bromo-2,6-difluoro-phenyl)-methanol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedures described in Example 121 and 54 to give the product as a colorless oil (9.22 g); MS (ISP): 480.3, 482.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21]CC)=[O:20]>CC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:18][C:19]([OH:21])=[O:20])=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
The mixture of 2-fluoro-4-hydroxybenzonitrile (274 mg, 2.1 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol) and acetone (25 ml) was refluxed for 6 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml of dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 1, and then extracted three times with ethyl acetate (20 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from ethanol and petroleum ether to give 268 mg 4-cyano-3-fluorophenoxyacetic acid as white crystals, mp 150-152° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([N:15]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17][CH2:16]2)=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[OH-].[Li+].C(O[C:29](OCC)(OCC)[CH2:30][CH3:31])C>CO>[N:18]12[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19]1)[N:15]([C:12]1[CH:11]=[C:3]3[C:2](=[CH:14][CH:13]=1)[N:1]=[C:29]([CH2:30][CH3:31])[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:4]3=[O:5])[CH2:16][CH2:17]2
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1C(=O)NCC(=O)O
Reactant: CCOC(CC)(OCC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2ccc(N3CCN4CCC3CC4)cc2c(=O)n1CC(=O)O
Temperature: 160 °C
Reaction time: 8 h

Procedure:
2-(2-Amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetic acid (85.3 mg, 0.27 mmol) (Intermediate 9A) (100 mg, 0.36 mmol) was dissolved in triethoxypropane (1 mL), and heated in the microwave at 160° C. for 10 minutes. Reaction allowed to cool to room temperature and lithium hydroxide solution added (0.5 mL, 1M in methanol) and reaction stirred overnight. Organic layer purified using a 1 g SCX cartridge, followed by preparative-HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford 2-(6-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-ethyl-4-oxoquinazolin-3(4H)-yl)acetic acid (76 mg, 0.21 mmol).
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[N+:14]([CH:17]([CH3:19])[CH3:18])([O-])=O.[OH-].[Na+].O.NN.O(C(C)C)C(C)C>CCO.[Ni].O.CC(O)=O>[NH:7]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:5]([CH2:4][C:17]([NH2:14])([CH3:19])[CH3:18])=[CH:6]1
Reactant: CC(C)[N+](=O)[O-]
Reactant: CN(C)Cc1c[nH]c2ccccc12
Agent: [Ni]
Agent: NN
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(N)Cc1c[nH]c2ccccc12
Reaction time: 8 h

Procedure:
A mixture of gramine (120.0 g., 0.69 mole), 2-nitropropane (443 ml.), and NaOH (28.8 g., 0.72 mole) was stirred and gradually heated to reflux under N2. After a 6.5 hour reflux period, the reaction mixture was allowed to stand at room temperature overnight, and then diluted with 600 ml. of 10% aqueous AcOH. The mixture was extracted with 1.5 l of Et2O, and the organic layer washed with H2O (4×500 ml.). Concentration of the Et2O solution in vacuum gave an oil which was dissolved in 500 ml. of 95% EtOH. This solution was diluted with 300 ml. of H2O. (Seeding and scratching early in the dilution kept the product from oiling out). After cooling, the yellow solid was collected on a filter to give 105 g. (70%) of nitro intermediate, m.p. 72°-74°. The nitro compound was dissolved in 1.3 l of 95% EtOH, and Raney nickel (70 g., EtOH-washed) and added. The mixture was heated to reflux, and a solution of 85% hydrazine hydrate (116 g., 2.3 mole) in 95% EtOH (110 ml.) was added dropwise at a rate to maintain gentle reflux. The mixture was then heated at reflux for an additional 1.5 hours, cooled, and filtered. Concentration of the filtrate gave crude product as a solid. A solution of the solid in 400 ml. of EtOAC was diluted with 500 ml. of (i-Pr)2O and cooled. The white, cottony solid which separated was collected on a filter to give 91 g., (100%) of product, m.p. 122°-126°. It was used in Procedure 26A without further purification.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:10][C:11]([O:13]CC)=[O:12].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].Cl>CC#N.O.CCO>[C:1]1([CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][CH2:10][C:11]([OH:13])=[O:12]
Reactant: Cc1ccccc1O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1OCC(=O)O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred solution of o-cresol (200 mg, 1.85 mmol) in MeCN (5 mL) was added ethyl bromoacetate (461 mg, 2.78 mmol) and K2CO3 (766 mg, 5.55 mmol). The mixture was stirred at 80° C. for 4 hours. The mixture was filtered and the filtrate concentrated. NaOH (150 mg, 3.70 mmol) and H2O/EtOH (1:1, 10 mL) was then added to the mixture and the mixture stirred at 50° C. for 4 hours. After cooling, the mixture was acidified by adding 1M HCl then extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was used directly in the next step without further purification.
Reaction SMILES: N1(C2C=CC(C([N:13]3[C:17]4[CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[S:20][C:16]=4[C:15]([NH:25][C:26](=[O:39])[C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[CH:29][CH:28]=4)=[N:14]3)=O)=CC=2)CCOCC1>CO.CCN(CC)CC>[N:33]1([C:30]2[CH:31]=[CH:32][C:27]([C:26]([NH:25][C:15]3[C:16]4[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:17]=4[NH:13][N:14]=3)=[O:39])=[CH:28][CH:29]=2)[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1
Reactant: COC(=O)c1cc2c(s1)c(NC(=O)c1ccc(N3CCOCC3)cc1)nn2C(=O)c1ccc(N2CCOCC2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc2[nH]nc(NC(=O)c3ccc(N4CCOCC4)cc3)c2s1

Procedure:
A mixture of methyl 1-(4-morpholin-4-ylbenzoyl)-3-[(4-morpholin-4-ylbenzoyl)amino]-1H-thieno[3,2-c]pyrazole-5-carboxylate (4.3 g, 7.5 mmol) in MeOH (200 ml) and Et3N (20 ml) was refluxed for 8 h. After cooling the precipitate was separated by filtration and triturated with hot methyl alcohol. After filtration and drying at 40° C. under vacuum 2.4 g of title compound were obtained. LC-MS, chromatographic method A, Rt 4.52, [M+H]+ 387.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:22].C(N(CC)CC)C.C1(OC)C=CC=CC=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:22])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: COc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (28 kg) and triethylamine hydrochloride (2.7 kg) were added to anisole (244 kg). N,N-Diisopropylethylamine (19.2 kg) was added, followed by a line wash of anisole (20 kg). The mixture was cooled to 15° C. and phosphorus oxychloride (19.8 kg) added over 5 minutes, followed by a line wash of anisole (13.9 kg). After stirring for 15 minutes the mixture was heated to 80° C. over 90 minutes and held at 80° C. for 1 hour. When the reaction was complete the batch was transferred to a new reactor, followed by a line wash of anisole (39.7 kg). The mixture was cooled to 40° C. and 16.19% w/w aqueous sodium hydroxide solution (132 kg) added over 15 minutes, allowing the temperature to rise to 50° C., followed by a line wash of water (5 kg). The mixture was held at 50° C. for 30 minutes, then heated to 80° C. The batch was filtered through a Gaf filter, followed by a line-wash of anisole (10 kg). The lower aqueous layer was separated and the upper organic layer washed at 80° C. with 20.9% w/w aqueous sodium chloride solution (98.2 kg). The mixture was distilled under reduced pressure (80 mbar) to leave a residual volume of 224 l. 1-Methyl-2-pyrrolidinone (28.9) was added and the mixture heated to 80° C. to give a solution of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](/[C:17](/[F:34])=[C:18](\[F:33])/[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=2)[CH2:9][CH:10](O)[CH2:11][Si](C)(C)C)=[CH:4][CH:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][CH:10]=[CH2:11])/[C:17](/[F:34])=[C:18](\[F:33])/[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CC(O)CC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Solvent: O
Solvent: CC(=O)O
Product: C=CCC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Yield: 94.2 %

Procedure:
(5E )-4-(4-chlorophenyl)-5,6-difluoro-7-(3-phenoxyphenyl)-1-(trimethylsilyl)-5-hepten-2-ol (0.194 g, 0.39 mmol) was dissolved in glacial acetic acid (8 ml) containing water (40 drops) and heated at 105° C. to 110° C. for six hours. The reaction mixture was concentrated in vacuo, the residue diluted with saturated aqueous so dium bicarbonate, and extracted with methylene chloride (3×25 ml). The combined organic extracts were washed with water (25 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to a yellow oil (0.16 g). Chromatography an a preparative thin layer silica gel plate developing with methylene chloride:hexane (1:1) afforded the title compound as a colorless oil (0.151 g) which is characterized by IR, 1HNMR and mass spectral analysis.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[NH3:19]>C1COCC1>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([NH2:19])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: N
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: NC(=O)c1csnc1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2.92 g (0.010 mol) of 3-(α,α,α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride in 10 ml of THF was added to a solution of excess ammonia gas in THF stirred in a dry ice acetone bath. The mixture was slowly warmed to 23° with stirring. The solid NH4Cl was removed by filtration, and the filtrate was concentrated to about 20 ml. Then 100 ml of ether was added, and the solution was extracted with two portions of 10% Na2CO3 solution and once with saturated NaCl solution. The ether layer was dried (CaSO4 ) and concentrated to 2.25 g (83%) of white solid, m.p. 141°-141.5°; infrared (mineral oil mull) 2.92, 3.11, 6.09, 6.11 μ.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:13][CH:14]=1
Reactant: COc1c(COc2ccc(N)cc2)cc(Br)cc1C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1c(COc2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
step 4—To a solution of 118 (0.20 g, 0.55 mmol) in pyridine (3 mL) cooled to 0° C. was added methanesulfonyl chloride (0.081 g, 0.71 mmol). Stirring was continued at 0° C. for 30 min then at RT for 3 h. The reaction mixture was diluted with EtOAc, washed sequentially with aqueous CuSO4 and 2N HCl, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.20 g (84%) of N-[4-(5-bromo-3-tert-butyl-2-methoxybenzyloxy)phenyl]methanesulfonamide (120) as a white solid.
Reaction SMILES: N12CCCCC1C=NCCC2.[CH3:12][C:13](=[CH:15][CH2:16][CH2:17][N+:18]([O-:20])=[O:19])[CH3:14].[C:21]([O:26][CH3:27])(=[O:25])/[CH:22]=[CH:23]/[CH3:24]>CO>[CH3:24][CH:23]([CH:17]([N+:18]([O-:20])=[O:19])[CH2:16][CH:15]=[C:13]([CH3:14])[CH3:12])[CH2:22][C:21]([O:26][CH3:27])=[O:25]
Reactant: CC(C)=CCC[N+](=O)[O-]
Reactant: C/C=C/C(=O)OC
Agent: C1=NCCCN2CCCCC12
Solvent: CO
Product: COC(=O)CC(C)C(CC=C(C)C)[N+](=O)[O-]
Reaction time: 144 h
Yield: 19.5 %

Procedure:
1,5-Diazabicyclo[5,4,0]undec-5-ene (4 ml) is added to a solution of 2-methyl-5-nitro-2-pentene (25.0 g, 0.193 m) in methanol (200 ml). The resulting mixture is heated to 60° and methyl crotonate (30.85 g, 0.308 m) is added under nitrogen. The mixture is then stirred for 6 days at 60° after which it is cooled to room temperature and most of the methanol is removed in vacuo. The residue is treated with ether (500 ml) and washed with 2 N HCl (250 ml) and water (250 ml). The organic layer is dried (Na2SO4) and evaporated in vacuo to give 42.5 g of crude product. The crude product is purified by column chromatography on silica gel (500 g, ethyl acetate/hexane 2:98) to give methyl 3,7-dimethyl-4-nitro-6-octenoate (8.65 g, 42%).