Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.Cl.[NH2:12][C:13]([NH2:15])=[NH:14].C(N(CC)CC)C>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:12]=[C:13]([NH2:15])[N:14]=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Br)cnc1F
Reactant: N=C(N)N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Nc1ncc2cc(Br)cnc2n1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
5-bromo-2-fluoronicotinaldehyde (3.0 g, 14.78 mmol), guanidine hydrochloride (1.69 g, 17.74 mmol) and triethylamine (4.48 g, 44.35 mmol) were dissolved in 1-methyl-2-pyrrolidinone (15 mL), and the reaction mixture was stirred at 180° C. for 15 min under microwave. The mixture was cooled to RT, quenched with water (200 mL) and extracted with ethyl acetate (2×300 mL). The organic layers were combined, washed with water (3×50 mL) and brine (3×50 mL), dried over sodium sulfate, filtered, and concentrated to afford a crude product, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether=3:1) to afford 6-bromopyrido[2,3-d]pyrimidin-2-amine (2.0 g, 60%) as a yellow solid. MS (ES+) C7H5BrN4 requires: 224, 226. Found: 225, 227 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[S:3]([CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[S:19][C:18]2[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:16][C:15](Cl)=[N:14][C:13]=2[CH:12]=1)(=[O:5])=[O:4].CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][CH:42]=[C:41]3[C:37]=2[CH:38]=[N:39][NH:40]3)O1>>[NH:40]1[C:41]2[C:37](=[C:36]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:18]4[S:19][C:11]([CH2:10][NH:9][CH2:8][CH2:7][CH2:6][S:3]([N:2]([CH3:27])[CH3:1])(=[O:5])=[O:4])=[CH:12][C:13]=4[N:14]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[N:39]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CN(C)S(=O)(=O)CCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(C)S(=O)(=O)CCCNCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
3-[(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-amino]-propane-1-sulfonic acid dimethylamide was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification by column chromatography yielded 385. NMR: CDCl3: 1.99-2.01 (2 H, m, CH2), 2.78-2.81 (2 H, m, CH2), 2.82 (6 H, s, Me), 2.98-3.01 (2 H, m, CH2), 3.84-3.88 (4 H, m, CH2), 4.02-4.05 (4 H, m, CH2), 4.07 (2 H, s, CH2), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar) and 9.03 (1 H, s, Ar). MS: (ESI+): MH+ 516.34
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=O)[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1.[NH:20]([C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)=[S:23])[NH2:21].CN(C)C=O>Cl.O>[OH:1][C:2]1[C:3]([C:17](=[N:21][NH:20][C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[S:23])[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)C)cc2)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C(C)C)cc2)c1O
Yield: 72 %

Procedure:
1-[4-Hydroxy-5-(4-isopropylphenyl)-1-methyl-1H-pyrazol-3-yl]ethanone (0.116 mmol, 29.9 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.116 mmol, 24.5 mg) were stirred with dimethylformamide (2 mL) and two drops of concentrated hydrochloric acid at room temperature for 24 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (37.7 mg, yield 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:21]=2)=[CH:9]\[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:21]=2)=[CH:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2ccccn2)cc1
Solvent: O
Product: Cc1ccc(C(=CCN2CCCC2)c2ccccn2)cc1
Reaction time: 3 h
Yield: 71.4 %

Procedure:
45 ml of demineralized water is charged into a round-bottomed flask kept at 25° to 30° C. and then slowly 405 ml of 90% Conc. H2SO4 is added and the temperature is raised to 40° C.-60° C. under stirring. Slowly 150 g of 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidinopropan-1-ol is charged and the temperature is maintained at 85° C. under stirring. The reaction mass is heated to 100-105° C. and the temperature is maintained for 4 hours under stirring. After completion of the reaction, the reaction mass is cooled to 25°-30° C. and then poured into ice cold water (3 litre) at 5-10° C. under stirring over a period of one hour. 50% NaOH solution (w/w) is added slowly to the reaction mixture while maintaining the temperature at 5° to 20° C. over a period of 2 hours and the contents are stirred for an hour at 25° to 30° C. The reaction mixture is filtered under suction to obtain 161 g wet triprolidine base comprising >92% E-isomer along with <8% Z-isomer. 1.5 litres of demineralized water and 161 g wet triprolidine base are charged into a round-bottom flask at 25° to 30° C. and the contents are stirred for 3 hours by maintaining the same temperature. The contents are filtered and dried under suction for 2 hours. The process is repeated thrice to obtain 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidino prop-1-ene (115 g, 82%) comprising of >98% E-isomer along with <2% of Z-isomer.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[N+:7]([O-:9])=[O:8].C(=O)(O)[O-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([N:6]1[C:2]([Br:1])=[C:3]([N+:7]([O-:9])=[O:8])[N:4]=[CH:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1nc[nH]c1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncn(Cc2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
A solution of the product of Example 312A (2.3 g, 11.98 mmol) in anhydrous N,N-dimethylformamide (40 mL) at 25° C. was reacted with sodium bicarbonate (2.0 g, 24 mmol) and dropwise addition of benzyl bromide (1.58 mL, 13.17 mmol). The reaction was stirred for an additional 12 hours at 25° C. The reaction was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography on a C18 column, eluting with a gradient of acetonitrile in water containing 0.1% trifluoroacetic acid (5:95 to 100) to give the title compound (1.63 g, 48%). MS (ESI+) m/z 284 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.38 (s, 2H), 7.24-7.42 (m, 5H), 8.28 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:9][C:8]2=O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:9]=[C:8]2[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cc2nc(-n3cc(C(=O)O)cn3)nc(N3CCOCC3)c2cc1Oc1c(C)cccc1C

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI/CI): predicted mass C25H25N5O4, 459.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH:36]2[CH2:38][CH2:37]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[CH:36]1([NH:35][S:32]([C:28]2[CH:27]=[C:26]([NH:25][C:22]([C:21]3[CH:20]=[N:19][N:12]4[C:13]([C:15]([F:17])([F:16])[F:18])=[CH:14][C:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)=[N:10][C:11]=34)=[O:24])[CH:31]=[CH:30][CH:29]=2)(=[O:34])=[O:33])[CH2:38][CH2:37]1
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NC2CC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 567.9 [(M−H)−]; mp 248° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([CH:14]([CH3:17])[CH:15]=C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]=[O+][O-].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([CH:14]([CH3:17])[CH2:15][OH:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=CC(C)C1(NC(=O)OCc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(CO)C1(NC(=O)OCc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
A solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1-methylallyl)piperidine-1-carboxylic acid 1-tert-butyl ester (25.5 g) in chloroform/methanol (250 ml/250 ml) cooled to −78° C. was flowed ozone air for 30 minutes. To the reaction mixture was added sodium borohydride (7.5 g) in small batches, and the mixture was warmed to room temperature. To the mixture was added 5% aqueous sodium bicarbonate solution (250 ml), and the mixture was extracted with chloroform (125 ml). The separated aqueous layer was extracted with chloroform (125 ml) again. The combined organic layer was sequentially washed with a mixed aqueous solution of sodium bicarbonate/sodium thiosulfate (12.5 g/25.0 g, 275 ml), water (125 ml) and 10% aqueous sodium chloride solution (125 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 2/3) to give the titled compound (21.9 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][O-:15].[Na+]>CO.O>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[O:15][CH3:14])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 95 %

Procedure:
0.200 g (1.00 mmol) of commercially available 2-chloro-1,3-dinitrobenzene was dissolved in a warm solution of 15 ml methanol and 0.223 g (4.13 mmol) of NaOMe. The reaction was stirred overnight with continued warming. The residue was dissolved in water after evaporation of the solvent. The aqueous solution was extracted with dichloromethane, dried and evaporated under reduced pressure to give 0.187 g of 2,6-dinitroanisole (95%) as yellow flakes. 1H NMR (CDCl3) δ 8.06 (d, J=8.2 Hz, 2H, Ar—H), 7.38 (t, J=8.2 Hz, 1H, Ar—H), 4.09 (s, 3H, O—CH3). 13C NMR (CDCl3) δ 148.0, 129.4, 124.2, 65.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:17]([OH:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:33](O)[CH3:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:17]([O:19][CH2:33][CH3:34])=[O:18])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)C(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 2.53 g (5.9 mmol) of 6-(p-chlorophenylsulfonamido)-2-[3-(3-pyridyl)propyl]-hexanoic acid in 150 mL ethanol is slowly added 1.5 mL (20.5 mmol) thionyl chloride and the reaction mixture is subjected to reflux for 8 hours. The solvent is evaporated and the residue is adjusted to pH 8 using 1N aqueous sodium hydroxide solution. The mixture is then extracted with methylene chloride (2×50 mL). Combined organic extracts are dried (MgSO4) and evaporated to give an oil which is then purified by flash chromatography using ether as the eluent to obtain ethyl 6-(p-chlorophenylsulfonamido)-2-[3-(3pyridyl)propyl]-hexanoate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][C:4]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCc1cc(CCO)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCc1cc(CCOS(C)(=O)=O)ccc1OC

Procedure:
1.2 g (0.0054 mol) of the compound 2d) from the previous step, 20 ml of dichloromethane, 0.75 ml (0.0054 mol) of triethylamine and, at 0-5° C., 0.42 ml (0.0054 mol) of methanesulfonyl chloride are placed in a round-bottom flask.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:19]([OH:21])=[O:20].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:20][C:19]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][C:15]([O:18][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)[C:8]=1[O:7][CH2:19][C:9]1[CH:10]=[CH:11][CH:12]=[CH:17][CH:8]=1)=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc2ccc(O)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc2ccc(OCc3ccccc3)cc2c1OCc1ccccc1

Procedure:
K2CO3 (2.88 g, 20.0 mmol), dry DMF (6.4 mL), 1,7-Dihydroxy-naphthalene-2-carboxylic acid (0.635 g, 3.11 mmol), and benzyl chloride (1.72 mL). Yield: 0.805 g of golden brown viscous product (55%, 2 steps).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5][O:4]1.Cl[C:11]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][N:19]=2)[CH:14]=[C:13]([Cl:21])[N:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:21][C:13]1[N:12]=[C:11]([NH:1][CH2:2][CH:3]2[CH2:8][NH:7][C:6](=[O:9])[CH2:5][O:4]2)[C:20]2[C:15](=[N:16][CH:17]=[CH:18][N:19]=2)[CH:14]=1
Reactant: NCC1CNC(=O)CO1
Reactant: Clc1cc2nccnc2c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1COC(CNc2nc(Cl)cc3nccnc23)CN1
Yield: 34 %

Procedure:
A solution of 6-(aminomethyl)morpholin-3-one (130 mg, 1 mmol), 5,7-dichloropyrido[4,3-b]pyrazine (200 mg, 1 mmol) and DIEA (260 mg, 2 mmol) in THF (20 mL) was stirred at reflux overnight. After concentration, the residue was purified by column chromatography to give product as yellow solid (100 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].C(=O)([O-])[O-].[Na+:12].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16].C(OCC)C>C(OCC)C.O>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:15]([NH:1][CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5])=[O:16])=[CH:24][CH:23]=1)([O-:27])=[O:26].[Na+:12]
Reactant: NCCS(=O)(=O)O
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(NCCS(=O)(=O)[O-])OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 70.7 %

Procedure:
A mixture of 2-aminoethanesulfonic acid (5.0 g) and sodium carbonate (9.4 g) in ethyl ether-water (100 mL, 1:1, v/v), at 0° C., was treated with 4-nitrobenzyl chloroformate (8.6 g). After stirring vigorously at 0° C. for 10 min and at room temperature for 15 hr, ethyl ether was added to the reaction mixture. The precipitates were collected by filtration and washed with ethyl ether to afford the title compound (9.2 g) as a white powder: 1H NMR (400 MHz, D2O) δ 2.94 (t, J=6.4 Hz, 2H), 3.39 (t, J=6.4 Hz, 2H), 5.09 (s, 2H), 7.44 (d, J=8.3 Hz, 2H), and 8.11 (d, J=8.3 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:17])=[CH:12][C:13]([Cl:16])=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][CH:20]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[C:21]([F:24])([F:23])[F:22]>>[C:3]([C:2]([NH:1][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([CH:20]([F:19])[C:21]([F:23])([F:24])[F:22])=[CH:33][CH:32]=1)([CH3:18])[CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:17])=[CH:12][C:13]([Cl:16])=[C:14]([Cl:15])[C:8]2=[N:7]1)#[N:4]
Reactant: O=C(Cl)c1ccc(C(F)C(F)(F)F)cc1
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (35 mg, described in Example 39) and 4-(1,2,2,2-tetrafluoroethyl)benzoyl chloride, the title compound was isolated as a solid (6.2 mg, 11%). MS (ES): M/Z [M+H]=508. NMR: (400 MHz, CHLOROFORM-d): 1.90 (s, 3H), 5.20 (d, J=13.8 Hz, 1H), 5.53 (d, J=13.8 Hz, 1H), 5.69 (dq, J=44.3 Hz, 5.9 Hz, 1H), 7.54 (br.s, 1H), 7.58 (s, 1H), 7.60 (d, J=8.1 Hz, 2H) and 7.98 (d, J=8.2 Hz, 2H). 19F NMR (376 MHz, CHLOROFORM-d): −197.6-−197.1 (m, 1F), −79.0 (q, J=5.9 Hz, 3F).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].O>CO>[C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH:2]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Cl
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2oc(C(=O)C=Cc3ccccc3)c(N)c2c1Cl
Temperature: 45 °C
Reaction time: 24 h
Yield: 92.6 %

Procedure:
A mixture of 7G (1.5 g, 6.26 mmol), benzaldehyde (0.863 g, 8.14 mmol, 1.3 eq) and NaOH (1.0 g, 25.04 mmol, 4 eq) in MeOH (20 mL) was stirred at 45° C. for 24 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (20 mL) The yellow solids precipitated out were collected by filtration and dried to give product 8A (1.9 g, 92.6% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:28])[C@H:9]([C:25]([OH:27])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:40][C@@H:41]([C:43]([O:45]CC1C=CC=CC=1)=[O:44])[CH3:42].C1N2CCN(CC2)C1.C1CCC(N=C=NC2CCCCC2)CC1>CCOCC.CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:28])[C@H:9]([C:25]([NH:40][C@@H:41]([C:43]([OH:45])=[O:44])[CH3:42])=[O:27])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N)C(=O)OCc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CN2CCN1CC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)N(C)C(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To 30 ml. of DMF were added 2.73 grams (7.1 mmoles) of Nα -t-butyloxycarbonyl-Nα -methyl-O-benzyl-L-tyrosine (prepared by acidification of 3.6 grams of the product from Part A and extraction into ether). The solution was cooled to 0° C., and 2.26 grams (7.1 mmoles) of the tosylate salt of D-alanine, benzyl ester, were added followed by 0.794 grams (7.1 mmoles) of triethylenediamine. The mixture was stirred at 0° C. for five minutes, and 0.96 grams of HBT and 1.46 grams (7.1 mmoles) of DCC were added. The mixture was stirred at 0° C. for two hours and then at room temperature for 24 hours. The mixture then was cooled to 0° C. and filtered. The filtrate was concentrated in vacuo to an oil, and then the oil was dissolved in ethyl acetate and extracted successively with 1 N aqueous sodium bicarbonate, water, 1.5 N citric acid, and water. The organic phase was dried over magnesium sulfate and concentrated in vacuo to an oil. The oil was dissolved in 60 ml. of ethanol, and 1.5 grams of 5% palladium on carbon were added to the mixture as a water slurry. Nitrogen was bubbled into the reaction mixture through a gas dispersion tube for five minutes followed by hydrogen gas for 24 hours. The mixture was flushed with nitrogen, and the catalyst was removed by filtration. The reaction mixture was concentrated in vacuo to an amorphous solid to give 2.5 grams (99 percent) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([F:19])=[CH:14][N:13]=1>>[Cl:11][C:12]1[N:17]=[C:16]([NH:8][CH:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:7])[C:15]([F:19])=[CH:14][N:13]=1
Reactant: CC(N)c1ccc(F)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: CC(Nc1nc(Cl)ncc1F)c1ccc(F)cc1

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-pyrimidineamine, 4-fluoro-α-methylbenzylamine and 2,4-dichloro-5-fluoropyrimidine were reacted to produce (±)-N-(2-chloro-5-fluoropyrimidinyl)-1-(4-fluorophenyl)ethylamine. 1H NMR (CDCl3): δ 7.87 (d, 1H, J=2.3 Hz), 7.37-7.33 (dd, 2H, J=5.4 and 8.4 Hz), 7.04 (t, 2H, J=8.4 Hz), 5.35-5.31 (m, 2H), 1.60 (d, 3H, J=6.4 Hz); LCMS: ret. time: 32.90 min.; purity: 98%; MS (m/e): 270 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:5]=1[NH:6][C:7](=[O:10])[CH2:8][Cl:9])([O-:3])=[O:2].[CH2:18]([O:21][CH2:22]Cl)[CH2:19][CH3:20]>C(Cl)Cl>[Cl:9][CH2:8][C:7]([N:6]([CH2:22][O:21][CH2:18][CH2:19][CH3:20])[C:5]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:4]=1[N+:1]([O-:3])=[O:2])=[O:10]
Reactant: CCCOCCl
Reactant: O=C(CCl)Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CCCOCN(C(=O)CCl)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Yield: 93 %

Procedure:
2.5 g. of 2',6'dinitro-2-chloroacetanilide, 3.0 ml. of chloromethyl n-propyl ether, 150 ml of methylene chloride and 1.1 gr. of phase transfer catalyst were charged to a round-bottom flask fitted with a mechanical stirrer. To the mixture was added 100 ml. of saturated NA2CO3 in one portion. The resulting mixture was stirred for three-quarter hour at which time GLC showed no starting material indicating the reaction was complete. The product, 2-chloro-2',6'-dinitro-N-(n-propoxymethyl)acetanilide was obtained as a yellow oil, (3.1 g., yield 93%)