Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:8])[C:4](=[O:7])[CH2:5][Cl:6].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:9]([NH:2][C@@H:3]([CH3:8])[C:4](=[O:7])[CH2:5][Cl:6])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@H](N)C(=O)CCl
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccccc1)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vigorously stirred suspension of (S)-3-amino-1-chloro-2-butanone, monohydrochloride (3.0 g., 19.0 mmole) in 150 ml. of tetrahydrofuran at 0°-5° is added, sequentially, benzoyl chloride (2.2 ml., 19.0 mmole), triethylamine (2.65 ml., 19.0 mmole), and sodium bicarbonate (1.6 g., 19.0 mmole). The reaction mixture is stirred for 15 minutes in the cold and then for 2 hours at room temperature. The solvent is evaporated and the residue is partitioned between ethyl acetate (400 ml.) and ice-water (40 ml.). The organic layer is washed with 5% potassium bisulfate (2×30 ml.) and water (3×30 ml.), then dried and evaporated. The resulting crystalline residue is recrystallized from benzene-petroleum ether giving three crops of comparable purity totaling 3.67 g.; m.p. 119.5°-121.5° (first crop), 118°-119.5° (third crop). A portion is recrystallized once more giving an analytically pure sample of (S)-3-(benzoylamino)-1-chloro-2-butanone; m.p. 119.5°-121°.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:10]([CH2:11][C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)=[O:13])[C:9]2[CH:27]=[CH:28][CH:29]=[CH:30][C:8]=2[N:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:6](=[O:37])[CH2:5]1.Br[CH2:39][C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[N:41]=1.O>CN(C=O)C>[C:52]([O:51][C:49]([N:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:40]([CH2:39][CH:5]2[C:4](=[O:3])[N:10]([CH2:11][C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][O:23][C:17]=4[CH:16]=3)=[O:13])[C:9]3[CH:27]=[CH:28][CH:29]=[CH:30][C:8]=3[N:7]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:6]2=[O:37])=[N:41]1)=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc2c(c1)OCO2
Reaction time: 22 h
Yield: 27.6 %

Procedure:
31 mg of Sodium Hydride (60% in oil) is added to a solution of 2-(-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(3,4-methylenedioxy-phenyl) acetamide (300 mg. 0.636 mmol) in DMF (10 mL ) and the resultant mixture stirred at RT for 0.5 h prior to the addition of 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole (197 mg, 0.636 mmol) to the reaction mixture. After 22 h, 10 mL of water is added and the resultant mixture extracted into ethyl acetate (3×10 mL). The combined organics were washed with water (3×10 mL), brine (10 mL), dried (MgSO4), and concentrated in vacuo to afford the crude product (460 mg) as a brown foam. Purification by silica gel flash column chromatography using 2% methanol in methylene chloride as eluent gave the desired product (123 mg) as a beige solid: 1H NMR (300 MHz, CDCl3) δ8.10 (d, 1H, J=8.6), 7.91 (d, 1H, J=8.0), 6.8-7.6 (m, 14H), 6.09 (s, 2H), 5.01 (m, 1H, J=6.9), 4.36 (m, 3H), 3.90 (dd, 1H, J=16.4, 8.8), 3.58 (m, 1H), 1.67 (s, 9H), 1.08 (m, 6H).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:54])[N:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:53])[CH2:34][NH:35][C:36]([O:38][CH2:39][CH:40]1[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C>Cl.C(OCC)(=O)C>[CH:42]1[C:41]2[CH:40]([CH2:39][O:38][C:36](=[O:37])[NH:35][CH2:34][C:33](=[O:53])[NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][CH2:24][N:22]([CH3:23])[C:21](=[O:54])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[CH:45]=[CH:44][CH:43]=1
Reactant: CN(CCc1ccccc1NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 117.4 %

Procedure:
N-{(1R)-1-[N-(2-{2-[2((Fluoren-9-ylmethoxycarbonyl)amino)acetylamino]phenyl}ethyl)-N-methylcarbamoyl]-2-(2-naphthyl)ethyl}N-methylcarbamic acid tert-butyl ester (1.18 g, 1.59 mnmol) was dissolved in 3.0 M hydrogen chloride in ethyl acetate (8 ml). The reaction mixture as stirred for 2.25 h at room temperature. The solvent was removed in vacuo. The residue as washed with diethyl ether (3×20 ml) and dried in vacuo to give 1.198 g of crude [(2-(2-[N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino]ethyl}phenylcarbamoyl)methyl]carbamic acid (fluoren-9-yl)methyl ester as hydrochloride, which was used for the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:62](=[O:64])[CH3:63])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH:67]1(O)[CH2:70][CH2:69][CH2:68]1>>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([N:61]([C:62](=[O:64])[CH3:63])[CH:67]2[CH2:70][CH2:69][CH2:68]2)=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: OC1CCC1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N(C(C)=O)C2CCC2)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (50 mg) was reacted with cyclobutanol according to General Procedure W to give (S)-2-({(S)-7-[2-(acetyl-cyclobutyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]-isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester. This product (16 mg) was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 964.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.CN(C)[CH2:17][CH2:18][CH2:19]N=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)CC>CN(C)C=O.O>[C:1]([C:4]1[CH:12]=[C:8]([C:9]([O:11][CH2:17][CH2:18][CH3:19])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCO
Product: CCCOC(=O)c1cc(C(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
5-Acetylsalicylic acid (360 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (458 mg), 1-hydroxybenzotriazole hydrate (36.7 mg), and propanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give propyl 5-acetylsalicylate (202 mg, yield 45%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:9]([N:17]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH:18]1[CH2:22][N:21]([CH2:23][CH3:24])[CH2:20][CH:19]1[OH:25])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+].O>CO>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:9]([N:17]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]1[CH2:22][N:21]([CH2:23][CH3:24])[CH2:20][C@H:19]1[OH:25])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN1CC(O)C(N(C(=O)c2ccccc2)C2CCCCC2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN1C[C@@H](O)[C@H](N(C(=O)c2ccccc2)C2CCCCC2)C1

Procedure:
A mixture of 4.8 g (9 mmole) of trans-benzoic acid ester with 4-[(benzoyl)(cyclohexyl)amino]-1-ethyl-3-pyrrolidinol fumarate [1:1], 1.7 g (30 mmole) of potassium hydroxide, 10 ml of water and 40 ml of methanol was heated on a steam bath for 1 hr. then concentrated to approximately 5-10 ml volume under reduced pressure. The residue was partitioned between water and methylene chloride and the organic layer was dried and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and 1.0 g fumaric acid added and the precipitate was collected. After recrystallization from ethyl acetate, 2.7 g (72%) of white powder, m.p. 145.0°-146.5° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])[CH:17]=[CH:18][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:26][C:24](=[NH:25])[CH2:23][O:22][CH2:21][CH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=1)=[O:6]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: N=C(N)COCCc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1cccc(Cl)c1)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 2-[2-(3-chloro-phenyl)-ethoxy]-acetamidine hydrochloride in the presence of TBTU and DIPEA to give 2,5-dichloro-N-{2-[2-(3-chloro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide as orange oil. MS: m/e=388.1 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]([NH2:16])=[O:15].C(N(CC)C(C)C)(C)C.[C:26]1([CH3:35])[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([CH3:35])=[CH:27][CH:28]=3)=[O:34])=[CH:11][CH:12]=2)[C:3]=1[C:14]([NH2:16])=[O:15]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nsc(N)c3C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69.3 %

Procedure:
A mixture of 5-amino-3-(4-aminophenyl)isothiazole-4-carboxamide (25 mg, 0.11 mmol), N,N-diisopropylethylamine (0.047 mL, 0.27 mmol), and para-tolyl isocyanate (0.016 mL, 0.13 mmol) in 0.9 mL DCM was reacted at room temperature. After 1 hour an additional 0.006 mL para-tolyl isocyanate was added, and then 0.004 mL at 3.5 hrs. At 21 hours the reaction was quenched with 1 mL MeOH, stirred 10 min at rt, and then evaporated. The residue was triturated with EtOAc which afforded the title compound as a pale yellow solid (28 mg, 72%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:34]2[C:29]([F:28])=[N:30][CH:31]=[CH:32][CH:33]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2Br)cn1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)cn1

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl({5-bromo-1-[(6-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (463 mg), (2-fluoropyridin-3-yl)boronic acid (172 mg), sodium carbonate (260 mg) and tetrakis(triphenylphosphine)palladium (176 mg), the title compound was obtained as a pale-yellow oil (yield 293 mg, 45%).
Reaction SMILES: C[Mg]Br.[F:4][C:5]1[N:16]=[C:15]([F:17])[CH:14]=[CH:13][C:6]=1[C:7](N(OC)C)=[O:8].[Cl-].[NH4+].[C:20](OCC)(=O)C>C1COCC1>[F:4][C:5]1[C:6]([C:7](=[O:8])[CH3:20])=[CH:13][CH:14]=[C:15]([F:17])[N:16]=1
Reactant: CCOC(C)=O
Reactant: CON(C)C(=O)c1ccc(F)nc1F
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(F)nc1F

Procedure:
A solution of methylmagnesium bromide in THF (0.96 M, 88.1 mL) was added to a solution of 2,6-difluoro-N-methoxy-N-methylnicotinamide (7.01 g) in tetrahydrofuran (180 mL) under ice-cooling, and the reaction solution was stirred under ice-cooling for two hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution under ice-cooling, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain 4.74 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[K].[S:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>CN1CCCC1=O>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][S:11]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Agent: [K]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N)n2)cc1
Yield: 66.8 %

Procedure:
0.98 g (0.006 mol) of 2-amino-4,6-dichloropyrimidine and 3.03 g (0.012 mol) of N-(4-sulfamoyl-phenyl)-acetamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water, the inorganic phase was saturated with sodium chloride and the remaining ethyl acetate dissolved in the aqueous was distilled off on a rotary evaporator. The aqueous phase was made acid with 1N HCl, the crystals which separated were filtered off under section and washed with water. After drying there were obtained 1.37 g (67%) of N-[4-(2-amino-6-chloro-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide as beige crystals; m.p.: 272-273° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:20]([OH:22])=O)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:23][C:24]1(C)OC(=O)CC(=O)[O:25]1.S([O-])(O)(=O)=O.[K+]>CN(C1C=CN=CC=1)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:24](=[O:25])[CH:23]=[C:20]([OH:22])[CH:11]2[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N[C@@H](Cc2ccc(F)cc2)C(=O)O)cc1Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(N2C(=O)C=C(O)C2Cc2ccc(F)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of N-(3-chloro-4-cyanophenyl)-4-fluorophenylalanine (3.67 g), Meldrum's acid (1.74 g) and 4-(N,N-dimethylamino)pyridine (2.11 g) in tetrahydrofuran (50 mL) was added N,N′-carbonyldiimidazole (2.24 g, 13.8 mmol) at 0° C., and the mixture was stirred at room temperature overnight. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), and the mixture was refluxed for 45 min. After allowing to room temperature, the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate-isopropyl ether to give the title compound as colorless crystals (yield: 2.54 g, 64%).
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])C=CC=CC=1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)(=O)C>[CH:20]1([NH:26][C:8]([NH:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])=[O:19])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(NOc1cccc(Cl)c1Cl)Oc1ccccc1
Reactant: NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(NOc1cccc(Cl)c1Cl)NC1CCCCC1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
4.00 g (13.4 mmole) of N-(2,3-dichlorophenoxy)carbamic acid phenyl ester synthesized in Reference Example 1 was dissolved in 60 ml of ethyl acetate. 3.32 g (33.5 mmole) of cyclohexylamine was added thereto, and the mixture was reacted at 60° C. for 12 hours. The reaction mixture was cooled to room temperature, and after an addition of 100 ml of ethyl acetate, it was washed with a 3% sodium hydroxide aqueous solution and then with a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane, whereby 2.84 g of the desired product was obtained as light brown crystals (yield: 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][C:14]([NH2:18])=[N:15][CH:16]=3)[N:11]([CH3:19])[N:10]=2)=[CH:5][C:4]=1[C:20]([F:23])([F:22])[F:21].[Cl:24]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>S(=O)(=O)(O)O>[Cl:24][C:8]1[CH:7]=[C:6]([C:9]2[C:17]3[C:12](=[N:13][C:14]([NH2:18])=[N:15][CH:16]=3)[N:11]([CH3:19])[N:10]=2)[CH:5]=[C:4]([C:20]([F:21])([F:23])[F:22])[C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2nn(C)c3nc(N)ncc23)cc1C(F)(F)F
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: O=S(=O)(O)O
Product: COc1c(Cl)cc(-c2nn(C)c3nc(N)ncc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Methoxy-3-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 111, step 1) (182 mg, 0.56 mmol) is dissolved in concentrated sulfuric acid (11 ml) to give a red solution. Trichloroisocyanuric acid (44 mg, 0.188 mmol) is added and the reaction mixture is stirred at room temperature overnight then poured onto ice-water. After stirring for 30 minutes, the resulting precipitate is collected by filtration, washed with water and dried under vacuum (45°) to afford the title compound as the sulfate salt.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=O)=[CH:5][CH:4]=1)#[N:2].C=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC>C(OCC)(=O)CCC>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: C=Cc1ccccc1
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Solvent: CCCC(=O)OCC
Product: N#Cc1ccc(C=Cc2ccccc2)cc1
Yield: 26.8 %

Procedure:
The procedure described in Example 1 is followed, except that 16.55 g (0.1 mol) of 4-cyanobenzoyl chloride, 13.02 g (0.125 mol) of styrene, 35.37 g (0.1 mol) of tri-n-octylamine, 50 ml of ethyl butyrate as the solvent and 0.0575 g (0.0001 mol) of bis-(dibenzylideneacetone)-palladium(O) are used. After a reaction time of 2 hours at 100° C., 5.5 g (0.0268 mol) of 4-cyanostilbene, corresponding to a yield of 26.8% of theory, are obtained; melting point 119° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[CH:10][C:11]([Se:17][Se:18][C:19]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:20]=2[C:21](O)=[O:22])=[C:12]([CH:16]=1)[C:13](O)=[O:14]>O1CCCC1>[CH:26]1[C:25]([F:28])=[CH:24][C:20]([CH2:21][OH:22])=[C:19]([Se:18][Se:17][C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:16][C:12]=2[CH2:13][OH:14])[CH:27]=1
Reactant: O=C(O)c1cc(F)ccc1[Se][Se]c1ccc(F)cc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(F)ccc1[Se][Se]c1ccc(F)cc1CO

Procedure:
To lithium aluminum hydride (0.89 g, 23 mmol) in dry tetrahydrofuran (20 mL) under argon at room temperature, 2,2′-diselenobis(5-fluorobenzoic acid) (116) (2.05 g, 4.70 mmol) dissolved in 10 mL of dry tetrahydrofuran was added dropwise. After refluxing for 50 minutes, the mixture was quenched with 20 mL of water and extracted with ethyl acetate. The aqueous solution was left sitting overnight with consequent precipitation of 815 mg (42%) of 137 as yellow needles with mp 112° C. IR (KBr) 3214 (broad), 1577, 1016, 874, 814 cm−1; 1H NMR (300 MHz) δ 7.52 (dd, J=8.2 Hz, 5.6 Hz, 1H), 7.24 (dd, J=9.8 Hz, 1H), 6.89 (dt, J=8.2 Hz, 3.1 Hz, 1 H), 4.69 (s, 2H), 2.06 (br s, 1H); mass spectrum, m/z (relative intensity) 410 (10, M+), 188 (23), 123 (16), 96 (100), 75 (16). Exact mass calcd for C14H12O2F280Se: 409.9134. Found: 409.9132.
Reaction SMILES: [CH:1](/[S:9](Cl)(=[O:11])=[O:10])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:13]([NH2:23])(=[O:22])([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14]>>[CH:1](/[S:9]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([S:13](=[O:22])(=[O:14])[NH2:23])=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Product: NS(=O)(=O)c1ccc(NS(=O)(=O)/C=C/c2ccccc2)cc1
Yield: 80 %

Procedure:
A solution of (E)-styrylsulfonyl chloride (10 mmol) and sulfanilamide (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 171-173° C., was obtained in 80% yield.