Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:19]([F:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14](=[O:16])[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[C:19]=1[F:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2S,3S)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (800 mg, 3.46 mmol; prepared according to J. Amer. Chem. Soc. 2005, 127, 15923-15932) in CH2Cl2 (35 mL) were added successively 3-chloro-2-fluorobenzylamine (0.435 mL, 3.46 mmol), HBTU (1.97 g, 5.19 mmol), DIPEA (1.21 mL, 6.92 mmol). After stirring at RT for 18 h, the reaction mixture was diluted with CH2Cl2 and the organics were washed with water (2×), 0.1N aqueous HCl (2×), aqueous NaHCO3 solution (2×) and brine, dried (phase separator) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (EtOAc/c-hexane 1:2 to 4:1 then EtOAc) to afford the title compound as a colorless wax. TLC Rf (EtOAc/c-hexane 1:1)=0.32; MS (LC/MS): 373 [M+H]+, 395 [M+Na]+, 767 [2M+Na]+; tR (HPLC conditions C): 4.42 min.
Reaction SMILES: CS(O[CH:6]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2)(=O)=O.[CH3:29][NH2:30]>>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([CH2:7][CH:6]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[NH:30][CH3:29])[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Reactant: CN
Product: CNC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1

Procedure:
A solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethyl methanesulfonate (250 mg, 0.62 mmol) in methyl amine (3 mL, 40% in water) was stirred at 90° C. for 12 h. The progress of reaction was monitored by LCMS. The reaction mixture was extracted with EtOAc. The organic layer was dried and concentrated to get the crude product, which was purified by reverse phase HPLC to obtain the 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-N-methyl-1-(pyridin-4-yl)ethanamine. 1H NMR (CDCl3, freebase): δ (ppm): 8.59 d (2H), 7.3 d (2H), 7.29 d (1H), 7.23 s (1H), 7.03 d (1H), 4.19 m (1H), 4.03 m (2H), 3.66 dd (2H), 2.8 m (3H), 2.6 m (1H), 2.55 s (3H), 2.47 s (3H), 2.18 s (3H). Chiral HPLC provided enantiomers 151a and 151b.
Reaction SMILES: O[CH:2]([C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[C:20]1([C:17]2[O:16][C:15]([CH:2]=[CH:3][C:4]3[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)C=Cc1cccc(CC(O)c2ccc(-c3ccccc3)o2)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C=Cc1cccc(C=Cc2ccc(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To acid (28) (9.2 mg, 0.028 mmol) in DCM (1 mL), externally cooled to −78° C., was added methanesulphonyl chloride, (20 mg, 0.17 mmol) and triethylamine (29 mg, 0.29 mmol). The solution was then allowed to warm to ambient temperature and stirred for a further 2 hours. The solvent was concentrated in vacuo and the residue purified by Flash Master Jones Chromatography using a 2 g silica cartridge and eluting with 50% EtOAc in heptane to give the title compound as a white solid. Yield: 3.6 mg, 41%; LC-MS tr 1.77 min; NMR Purity: >85%; MS (ES+) m/z 317 (M+H); 1H NMR (400 MHz; DMSO): δ 6.70-6.80 (m, 2H), 7.15 (d, 1H), 7.25-7.35 (d, 1H), 7.35-7.45 (m, 2H), 7.50-7.60 (m, 4H), 7.65-7.75 (m, 3H), 7.90 (d, 2H), 8.10 (s, 1H)
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)C1C=CC=CC=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[CH3:44][S:45]([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:18])[CH2:13][CH2:12][N:11]1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=1)(=[O:47])=[O:46]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COCc2ccccc2)cc1)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COS(C)(=O)=O)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A 25-mL round bottomed flask was charged with 1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (400 mg, 0.888 mmol, Example 44), triethylamine (136 μL, 0.977 mmol) and CH2Cl2 (5 mL). After cooling to 0° C., methanesulfonyl chloride (69.2 μL, 0.888 mmol) was slowly added via syringe. The reaction was then warmed to room temperature and stirred for 3 h. After this time, the mixture was concentrated and the crude material was purified by column chromatography (12 g silica gel, 5%-80% (10% MeOH—CH2Cl2) in CH2Cl2) to give (4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (403 mg) as a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[S:19]([O:12][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: COc1cccc(CCCO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1cccc(CCCOS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of 3-(3-methoxyphenyl)-propanol (69 g, 0.42 mole) and pyridine (400 mL) was stirred at 5° C. as p-toluenesulfonyl chloride (87 g, 0.46 mole) was added portionwise. The reaction mixture was stirred at room temperature for 2 hours, then was poured onto ice/concentrated HCl and was extracted with ether. The extracts were washed with 2N HCl, wawter, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated to yield 126 g yellow oil, (95%); M+ 320.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C[O-].[Na+].[Na].[O:9]=[C:10]([CH:22]=[CH2:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>CO>[O:9]=[C:10]([CH2:22][CH2:23][CH2:4][N+:1]([O-:3])=[O:2])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C[N+](=O)[O-]
Reactant: C=CC(=O)CCCCCCCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CCCCCCCC(=O)CCC[N+](=O)[O-]
Temperature: -20 °C

Procedure:
Nitromethane (12.8 g; 0.21 mole) is added dropwise to a solution of sodium methoxide, prepared from sodium (4.6 g; 0.2 mole) and methanol (200 ml), at 0°-5° C. The solution is cooled to -20° C. and 9-keto-10-undecanoic acid, methyl ester (III) (21.2 g; 0.1 mole) is added dropwise into the solution over 5 hours.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[P:18](=[N:31][C:32](N1C=CN=C1)=[O:33])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[P:18](=[N:31][C:32](=[O:33])[O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccccc1P(=NC(=O)n1ccnc1)(c1ccccc1)c1ccccc1
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1P(=NC(=O)OCc1cccnc1)(c1ccccc1)c1ccccc1

Procedure:
A 760 mg portion of 3-pyridinemethanol, 35 ml of 1,2-dimethoxyethane, 340 mg of 50% sodium hydride in oil and 2.7 g of 1-[[[(2-methylphenyl)diphenylphosphoranylidene]amino]carbonyl]-1H-imidazole were reacted as described in Example 8, giving 2.05 g of the desired product, mp 142°-143° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(=O)c2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)NC1CCC(O)c2sccc21

Procedure:
In the same manner as described in reducing the (-)-4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea, (+)-4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea is reduced with NaBH4 to afford isomer B of the title compound, m.p. 216°-217° C. (dec.), [α]D25.5 =+18.51° (c, 2.11 in methanol). This isomer is 95% pure by high pressure liquid chromatography. Isomer A of the title compound is also purified by high pressure liquid chromatography as a 90-95% pure material, m.p. 160°-164° C. (dec.), [α]D24.5 =-91.03° (c, 2.2 in methanol). The cis and trans configurations for isomers A and B have not been determined unequivocally.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>CCOCC>[CH3:9][O:8][C:5]1[N:4]=[C:3]([O:10][CH3:11])[C:2]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)=[CH:7][N:6]=1
Reactant: COc1ncc(Br)c(OC)n1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Product: COc1ncc(C2(O)CCC3(CC2)OCCO3)c(OC)n1

Procedure:
The title compound was prepared as a white solid from 5-bromo-2,4-dimethoxy-pyrimidine (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)=[O:8].[NH:22]1[CH2:25][CH:24]([NH:26][C:27](=[O:44])[CH2:28][NH:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][CH:12]([N:22]2[CH2:23][CH:24]([NH:26][C:27](=[O:44])[CH2:28][NH:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:41])([F:43])[F:42])[CH:38]=4)[N:33]=[CH:32][N:31]=3)[CH2:25]2)[CH2:11][CH2:10]1)=[O:8]
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: COc1ccc(CNC(=O)C2CCC(=O)CC2)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc(CNC(=O)C2CCC(N3CC(NC(=O)CNc4ncnc5ccc(C(F)(F)F)cc45)C3)CC2)c(OC)c1

Procedure:
Reaction of N-(2,4-dimethoxybenzyl)-4-oxocyclohexanecarboxamide with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=O)[S:27][CH:28]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:10]([O:9][C:7]([NH:6]/[C:5](=[CH:29]\[C:26]1[S:27][CH:28]=[C:24]([Br:23])[CH:25]=1)/[C:3]([O:2][CH3:1])=[O:4])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=Cc1cc(Br)cs1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)/C(=C/c1cc(Br)cs1)NC(=O)OCc1ccccc1
Yield: 67.9 %

Procedure:
The title compound was prepared according to the method of Example 94a, employing N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (10.0 g, 30.2 mmol), 4-bromothiophene-2-carbaldehyde (7.52 g, 39.4 mmol), and DBU (5.34 g, 35.1 mmol) in dry dichloromethane (200 mL). Recrystallization from 4:1 (v/v) hexane/ethyl acetate afforded the title compound (8.13 g, 20.5 mmol, 68%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.71 (s, 3H), 5.12 (bs, 2H), 7.10-7.51 (bm, 5H), 7.59 (s, 1H), 7.71 (s, 1H), 7.87 (s, 1H), 8.98 (bs, 1H). MS APCI, m/z=354, 352. LC/MS: 2.53 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([C:26]2[O:25][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccco1
Reactant: COC(=O)Cc1c(C(=O)c2ccc(Br)cc2)[nH]c2cc(Cl)ccc12
Product: COC(=O)Cc1c(C(=O)c2ccc(-c3ccco3)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 207 from methyl[6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (Example 206) and furan-2-boronic acid.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>ClCCl>[CH3:24][S:25]([O:11][CH2:10][CH2:9][S:8][C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: OCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-(triphenylmethylthio)ethanol (2.66 g, 8.30 mmol) in cold (0° C.) dichloromethane (39 mL) kept under a nitrogen atmosphere was added methanesulfonyl chloride (0.704 mL, 9.10 mmol); the resulting mixture was treated dropwise (15 min) with triethylamine (1.34 mL, 9.6 mmol). After stirring for 15 min, the cooling bath was removed and the reaction mixture was stirred for 7 h then washed successively with water (10 mL), 0.5N citric acid (10 mL), water (10 mL), saturated sodium bicarbonate and water. The organic extracts were dried (MgSO4 -MgO) and concentrated under reduced pressure to a thick syrup which crystallized on standing. Trituration of the crystals in ether afforded white solid 2.1 g (63%) mp 95°-8° C.; ir (KBr) νmax : 1580, 1565 (phenyl), 1350, 1175, 1165 cm-1 (sulfonate); 1Hmr (CDCl3): 251 (2H, t, J=6.6 Hz, CH2S), 3.07 (3H, s, CH3SO3), 3.87 (2H, t, J=6.6 Hz, CH2O), 7.34 (15H, m, phenyl).
Reaction SMILES: Cl.NO.C([N:7](CC)C(C)C)(C)C.C(OC(=O)[NH:17][C:18](=S)[NH:19][C:20]1[C:25]([Br:26])=[CH:24][CH:23]=[CH:22][N:21]=1)C>CO.C(O)C>[Br:26][C:25]1[C:20]2[N:21]([N:7]=[C:18]([NH2:17])[N:19]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ncccc1Br
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2c(Br)cccn2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 40466.1 %

Procedure:
To a solution of hydroxylamine hydrochloride (0.10 kg, 1.4 mol, 5.0 equiv) and N,N-diisopropylethylamine (112 g, 0.867 mol, 3.00 eq) in 1:1 methanol/ethanol (1.5 L) was added ethyl[(3-bromopyridin-2-yl)carbamothioyl]carbamate (88 g, 0.29 mmol, 1 equiv) in one portion at room temperature. After 2 h, the reaction mixture was warmed to 60° C. for overnight. The reaction mixture was concentrated in vacuo, and water was added to the resulting residue. The solids were filtered and rinsed sequentially with 4:1 methanol/diethyl ether and diethyl ether to provide product as an off-white solid (25 g, 40%). LCMS (ESI) m/z: 212.8; 1H NMR (400 MHz, DMSO-d6) δ: 8.55 (m 1 H), 7.70 (m, 1 H), 6.75 (m, 1 H), 6.20 (br s, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[CH2:18](C(C(OCC)=O)C(OCC)=O)[CH:19]=C>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH2:12][CH:18]=[CH2:19])[C:9]([OH:11])=[O:10]
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Product: C=CCC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1

Procedure:
N-(3,5-Difluoro-benzyl)-2-allyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl allyl-malonate.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:21][C:20]3[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:18][C:17](Cl)=[N:16][C:15]=3[CH:14]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[NH2:30][C:31]1[N:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:19]2[C:20]3[S:21][C:13]([CH2:12][N:9]4[CH2:10][CH2:11][N:6]([S:3]([N:2]([CH3:29])[CH3:1])(=[O:5])=[O:4])[CH2:7][CH2:8]4)=[CH:14][C:15]=3[N:16]=[C:17]([C:34]3[CH:33]=[N:32][C:31]([NH2:30])=[N:36][CH:35]=3)[N:18]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CN(C)S(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CN(C)S(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-sulfonic acid dimethylamide (Example 28) was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester in General Procedure A. Purification on silica yielded 112. NMR (CDCl3): 2.51-2.55 (4H, m CH2), 2.75 (6H, s, Me), 3.22-3.25 (4H, m, CH2), 3.77 (2H, s, CH2), 3.78-3.82 (4H, m, CH2), 3.94-3.97 (4H, m, CH2), 5.14 (2H, br s, NH2), 7.20 (1H, s, Ar) and 9.20 (2H, s, Ar). MS: (ESI+): MH+=520.34.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH3:16][S:17][CH2:18][CH2:19][NH2:20].CO.C(OC(C)C)(C)C>>[CH3:16][S:17][CH2:18][CH2:19][NH:20][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: CSCCN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CSCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Yield: 66.7 %

Procedure:
A mixture of trans-stilbene oxide (1.18 g, 0.006 mol) and 2-(methylthio)ethylamine (0.78 g, 0.0085 mol) was heated at 140° C. in an oil bath for 15 hours. The cooled solid reaction mixture was triturated with isooctane and the red-brown solid collected. This was triturated with methanol-isopropyl ether giving an off-white solid (1.15 g, 67% yield); mp 163°-165° C.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].CC(O)=O.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:13]([NH:20][CH2:2][CH2:1][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: C=Cc1ncccn1
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(CNCCc2ncccn2)cc1

Procedure:
To a solution of 2-vinylpyrimidine (1.55 g, 14.6 mmol) in EtOH (15 mL) at room temperature was added AcOH (2.0 mL) and benzylamine (3.14 g, 29.3 mmol) (3.2 mL). The reaction mixture was heated to reflux for 18 h, and concentrated. Diluted with EtOAc, washed with 5 M NaOH (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 2% to 10% MeOH in DCM) gave N-benzyl-2-(pyrimidin-2-yl)ethanamine.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N+:3]=1[O-:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccnc(C)c1C
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c(C)c1C

Procedure:
A solution of 14 g of 2,3,4-trimethylpyridine in 140 ml of methylene chloride is treated cautiously while cooling with ice with 21 g of m-chloroperbenzoic acid. The reaction mixture is boiled at reflux for 1 hour, then made basic with a saturated soda solution and subsequently extracted. The organic phase is dried and concentrated. The residue is purified on a silica gel column, the medium pressure flash chromatography method (solvent: methylene chloride/methanol [5:1 ) being used and the pressure being produced with nitrogen gas. The 2,3,4-trimethylpyridine N-oxide obtained is processed directly.
Reaction SMILES: [CH2:1]([CH2:4][C:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[C:12]([O:14][C:15](=[O:16])[CH:6]21)=[O:13])[CH:2]=[CH2:3].[CH2:17]([NH2:20])[CH:18]=[CH2:19]>>[CH2:17]([N:20]=[C:15]([CH:6]1[CH:7]([C:12]([OH:14])=[O:13])[CH:8]2[CH2:11][C:5]1([CH2:4][CH2:1][CH:2]=[CH2:3])[CH:10]=[CH:9]2)[OH:16])[CH:18]=[CH2:19]
Reactant: C=CCCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: C=CCN
Product: C=CCCC12C=CC(C1)C(C(=O)O)C2C(O)=NCC=C

Procedure:
A mixture of 30 g of allylmethylbicyclo[2.2.1]hept-5-ene2,3-dicarboxylic anhydride and 9.41 g of allylamine is heated at reflux temperature for 2 hours, water is removed by distillation, and the product is rectified at 119°-127° C. and 2.66 Pa. This gives 30.24 g (85.5% of theory) of a pale yellow oil having the following characteristic data: nD20 =1.5202, η25 =0.135 Pa.s.
Reaction SMILES: Cl[CH2:2][CH:3]([O:6][CH3:7])[O:4][CH3:5].[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+]>O>[CH3:5][O:4][CH:3]([O:6][CH3:7])[CH2:2][NH:14][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC1CCCCC1
Reactant: COC(CCl)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(CNC1CCCCC1)OC
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-1,1-dimethoxyethane (206 mL) was treated with cyclohexanamine (575 mL) and the mixture was heated at 120° C. for 24 h under an atmosphere of nitrogen before being cooled to room temperature. A solution of sodium hydroxide (100 g) in 400 mL water was added, the mixture was stirred at room temperature for 10 min and then the layers were separated. The organic fraction was purified by distillation under reduced pressure (b.p. 105-107° C., 13 mm Hg) to give the title compound as a colourless oil (280 g). 1H NMR (400 MHz, CDCl3) δ 4.46 (t, J=5.5 Hz, 1H), 3.38 (s, 6H), 2.75 (d, J=5.6 Hz, 2H), 2.45-2.35 (m, 1H), 1.92-1.57 (m, 5H), 1.31-1.00 (m, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[Cl:18][S:19](O)(=[O:21])=[O:20]>C(Cl)Cl>[O:16]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:17])[N:7]1[CH2:6][C:2]1[S:1][C:5]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccs1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)Cl)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a cold (−78° C.) solution of 2-(thien-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (6.78 g, 27.87 mmol) in DCM (56 mL) was added dropwise (in about 10 min) chlorosulfonic acid (16.237 g, 139.3 mmol, 9.33 mL, d: 1.74) diluted in DCM (9.3 mL). The reaction mixture was stirred 2 h at −78° C., then 1 h at −40° C. and overnight at rt. The resulting brown solution was poured on ice. The mixture was extracted with DCM (3×200 mL), and the combined organic layers were washed with water (3×200 mL), dried over MgSO4, filtered and concentrated to afford a yellowish oil. This crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 1/4 to 1/3 to 1/2 in about 1 h) to give the title compound as a white solid (6.42 g, 67%). 1H NMR (CDCl3, 300 MHz) δ 7.89 (d, 1H. J=5.5 Hz), 7.87 (d, 1H. J=5.5 Hz), 7.76 (d, 1H, J=5.5 Hz), 7.75 (d, 1H, J=5.5 Hz), 7.71 (d, 1H, J=4.0 Hz), 7.18 (d, 1H, J=4.0 Hz), 5.05 (s, 2H). HPLC (Condition A), Rt: 4.6 min (HPLC purity: 94.8%).