Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:17])#[N:2].[C:18]([O-])(=[O:20])C.[Na+].C(O)(=O)C.C=O.C([O-])(O)=O.[Na+]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[C:14]([CH2:18][OH:20])=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: N#Cc1ccc(C2CCc3nccn32)cc1F
Reactant: CC(=O)[O-]
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(C2CCc3ncc(CO)n32)cc1F

Procedure:
A solution of product from Step H (3.79 g, 16.7 mmol), sodium acetate (2.44 g, 29.7 mmol), acetic acid (1.82 mL, 31.9 mmol), and formaldehyde (37% in water, 15.1 mL) was heated to reflux for 96 hours. The reaction was slowly neutralized by the addition of sat. aq. NaHCO3. The aqueous layer was extracted with methylene chloride (5×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (1→10% MeOH/CHCl3) to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([O:20][CH2:21][CH3:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1.COC(=O)C(OC)CC1C=CC=C(O)C=1>>[CH3:1][O:2][C:3](=[O:23])[CH:4]([O:20][CH2:21][CH3:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Agent: COC(=O)C(Cc1cccc(O)c1)OC
Product: CCOC(Cc1ccc(O)cc1)C(=O)OC

Procedure:
The title compound was prepared from 3-(4-Benzyloxy-phenyl)-2-ethoxy-propionic acid methyl ester (Preparation 2, step 3) via the same procedure used for the preparation of 3-(3-Hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (example 9, step 4) to produce a yellow oil. MS (ES) for C12H16O4 [M+H]+: 225.2, [M+NH4]+: 242.2, [+Na]+: 247.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>O1CCCC1>[F:12][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][C:20](=[O:22])[CH3:21])[CH:3]=1)[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: CC(=O)Cl
Reactant: Nc1cc(F)cc2c1NC(=O)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(F)cc2c1NC(=O)C2
Temperature: 0 °C
Yield: 96.1 %

Procedure:
A stirred solution of 7-amino-5-fluoro-1,3-dihydro-indol-2-one (1.0 g, 6 mmol) obtained from Example 4 in 30 ml of tetrahydrofuran was added with triethylamine (1.3 ml, 9 mmol). The solution was cooled down to 0° C. in an ice-water bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. The resulting mixture was heated to reflux for 1.5 hours and cooled until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-acetamide (1.2 g, 96%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C[O:18][C:19]([C:21]1[S:22][C:23]([CH2:26]Br)=[CH:24][CH:25]=1)=[O:20]>>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:26][C:23]2[S:22][C:21]([C:19]([OH:20])=[O:18])=[CH:25][CH:24]=2)=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Reactant: COC(=O)c1ccc(CBr)s1
Product: O=C(O)c1ccc(COc2ccc(-c3ccccc3[N+](=O)[O-])cc2)s1

Procedure:
5-(2′-Nitro-biphenyl-4-yloxymethyl)-thiophene-2-carboxylic acid was prepared using general procedure A from 4-hydroxy-2′-nitrobiphenyl (available from TCI America, Portland, Oreg.) and 5-bromomethyl-thiophene-2-carboxylic acid methyl ester (Intermediate 7). Yield: 80 mg. Mass spectrum (ES) MH+=356.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH3:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([CH3:29])[S:26][C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OC([N:11]1[CH2:18][C@H:17]2[C@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][CH2:15][CH2:16]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[C:23]([O:22][C:20]([NH:19][C:13]12[CH2:14][CH2:15][CH2:16][CH:17]1[CH2:18][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@]12CCC[C@H]1CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC12CCCC1CNC2
Yield: 104.4 %

Procedure:
A 10% palladium-carbon catalyst (about 50% wet, 114 mg) was added to a solution of (−)-(1R*,5S*)-3-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (569 mg, 1.579 mmol) in methanol (30 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for two hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure to give crude 1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (373 mg) as a colorless transparent gummy solid.
Reaction SMILES: [CH:1]1C=CC2N(O)N=N[C:5]=2[CH:6]=1.ClC1C=C2C(=CC=1)NC([C:21](O)=[O:22])=C2.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.[Cl:44][C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[NH:50][C:49]([C:54]([NH:56][CH:57]1[CH2:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[N:59]([CH2:67][C:68](=[O:75])NC3SC=NN=3)[C:58]1=[O:76])=[O:55])=[CH:48]2>C(Cl)Cl.CCOC(C)=O>[Cl:44][C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[NH:50][C:49]([C:54]([NH:56][CH:57]1[CH2:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[N:59]([CH2:67][C@@H:68]3[CH2:21][O:22][C:6]([CH3:5])([CH3:1])[O:75]3)[C:58]1=[O:76])=[O:55])=[CH:48]2
Reactant: On1nnc2ccccc21
Reactant: O=C(CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21)Nc1nncs1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)OC[C@@H](CN2C(=O)C(NC(=O)c3cc4cc(Cl)ccc4[nH]3)Cc3ccccc32)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
HOBT (209 mg, 1.55 mmol), 5-chloroindole-2-carboxylic acid (303 mg, 1.55 mmol), DIPEA (0.27 mL, 1.55 mmol) and then EDCI (370 mg, 1.94 mmol) were added to a solution of 3-amino-1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3,4-dihydroquinolin-2(1H)-one (Method 8, 428 mg, 1.55 mmol) in DCM (10 mL). The reaction was stirred for 18 h at ambient temperature, diluted with EtOAc (20 mL), washed with 1 N NaOH (15 mL), 0.1 N HCl (15 mL), saturated aqueous NaHCO3 solution (15 mL), dried (Na2SO4) and the volatiles removed under reduced pressure to give the title compound (684 mg, 97%) as a pale yellow solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]([OH:25])=O)=[CH:14]1.[O:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH2:27]([O:26][C:30](=[O:2])[CH2:29][C:23](=[O:25])[CH2:22][C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][CH:14]=1)[CH3:28]
Reactant: C1CCOC1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CCOC(=O)CC(=O)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
24.95 g (154 mmol) of carbonyldiimidazole are added at 0° C. to a solution of 24.5 g (140 mmol) of 3-indolyl-acetic acid in 250 ml of tetrahydrofuran and the mixture is stirred at 0° C. for 30 minutes. 46 g (161 mmol) of bis-(malonic acid monoethyl ester)magnesium salt are then added and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated by evaporation, and ice-cold 6N hydrochloric acid is added; diethyl ether is added and the organic phase is separated off. The organic phase is washed with aqueous 10% sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated by evaporation. The title compound is obtained in the form of an orange oil. 1H-NMR (200 MHz): 8.22 (br. s, 1H), 7.53 (d, 1H), 7.37 (d, 1H), 7.28-7.10 (m, 3H), 4.23 (q, 2H), 3,93 (s, 2H), 3.46 (s, 2H), 1.22 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH3:10]>C1COCC1>[Br:1][C:2]1[C:3]([NH2:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: N
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: C1CCOC1
Product: Nc1nc(Cl)ncc1Br
Reaction time: 15 h

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (25g, 110 mmol) in 200 mL THF is treated with 47 mL of ammonia (330 mmol, 7.0M solution in methanol). After stirring for 15 hours the solution is concentrated under reduced pressure and purified by short-filtration (SiO2, Hexanes: Ethyl acetate/1:1) to yield 21g (92%) of 1 as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:54])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([C:39](=[O:53])[C:40]1[CH:45]=[C:44]([NH:46][C:47](=[O:49])[CH3:48])[CH:43]=[CH:42][C:41]=1[N:50]=[N+]=[N-])[CH2:29][C:30](=[O:38])NC1CCCCC1>ClCCCl>[CH3:20][O:21][C:22](=[O:54])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:39](=[O:53])[C:40]2[CH:45]=[C:44]([NH:46][C:47](=[O:49])[CH3:48])[CH:43]=[CH:42][C:41]=2[NH:50][C:30](=[O:38])[CH2:29]1
Reactant: COC(=O)CCCCCN(CC(=O)NC1CCCCC1)C(=O)c1cc(NC(C)=O)ccc1N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: COC(=O)CCCCCN1CC(=O)Nc2ccc(NC(C)=O)cc2C1=O
Temperature: 50 °C
Yield: 58.2 %

Procedure:
500 mg polymerbound triphenylphosphine (Fluka #93093) was added to 267 mg (0.55 mmol) 6-{(5-acetylamino-2-azido-benzoyl)-cyclohexylcarbamoylmethyl-amino}-hexanoic acid methyl ester in 8 ml 1,2-dichloroethane. The suspension was heated to 50° C. for 120 min and the solvent was filtered off. The solid was collected, suspended in a solution consisting of 8 ml AcOH, 1 ml water, and 1 ml dioxane and the mixture was heated to reflux for 24 h and filtered. The filtrate was concentrated in vacuo and the residue flashchromatographed on silicagel in EtOAc/hexane as eluent to yield 6-(7-acetylamino-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-hexanoic acid methyl ester (117 mg, 0.32 mmol): MS (ISP) 362(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](OC(C)(C)C)=[O:11])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1.C[O-].[Na+].O>CO>[Br:17][C:5]1[CH:6]=[C:7]2[C:2](=[N:3][CH:4]=1)[NH:1][C:10](=[O:11])[CH:9]=[CH:8]2
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(Br)cnc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1ccc2cc(Br)cnc2[nH]1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A solution of (E)-tert-butyl 3-(2-amino-5-bromopyridin-3-yl)acrylate (2.5 g, 8.35 mmol) in anhydrous methanol (50 mL) was treated with sodium methoxide (8.5 mL of a 4.9 M solution, 41.75 mmol). The solution was heated at reflux for 2 h then cooled to room temperature. The mixture was cooled in an ice-H2O bath and treated with H2O (100 mL) under rapid stirring to give a precipitate. The solid was filtered and washed with H2O (20 mL). The filtrate was neutralized with 1 M HCl(aq) to form a precipitate. The solid was filtered and washed with H2O (20 mL). The solids were combined and dried under reduced pressure to give an off-white solid (1.75 g, 93%). 1H NMR (300 MHz, DMSO-d6) δ 8.43 (d, 1H, J=2.5 Hz), 8.06 (d, 1H, J=2.5 Hz), 7.60 (d, 1H, J=9.1 Hz), 6.44 (d, 1H, J=9.1 Hz); ESI MS m/z 225 (100%); 227 (100%)[C8H5N2OBr+H]+
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(O)cc4)[nH]c3cc21
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(OS(C)(=O)=O)cc4)[nH]c3cc21

Procedure:
2 g. (6.5 mmole) 8,8-dimethyl-2-(4-hydroxyphenyl)-5,6,7,8-tetrahydro-lH-imidazo[4,5-g]quinolin-6-one (see Example 30 d)) were suspended in 10 ml. water and, while cooling with ice, 5 ml. (65 mmole) methanesulphonic acid chloride and 50 ml. 2N aqueous sodium hydroxide solution were alternatingly added dropwise thereto in such a manner that a pH value of about 10 to 13 was always present. When the reaction was completed, the reaction mixture was filtered off with suction, the product was washed with water and purified by column chromatography (elution agent: methylene chloride/ methanol/acetic acid; 10:1:0.2 v/v/v). The evaporation fractions were suspended in water, rendered ammoniacal and washed with water to give 1.5 g. (68% of theory) of the title compound; m.p. 209 -215° C.
Reaction SMILES: [N:1]([C@H:4]1[CH2:7][C@H:6]([C:8]([OH:10])=O)[CH2:5]1)=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[N:1]([C@H:4]1[CH2:7][C@H:6]([C:8]([Cl:14])=[O:10])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H]1C[C@H](C(=O)O)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=N[C@H]1C[C@H](C(=O)Cl)C1
Temperature: 23 °C

Procedure:
To a solution of trans 3-azidocyclobutanecarboxylic acid (0.58 g, 4.1 mmol) in dichloromethane (10 ml) was added oxalyl chloride (0.45 ml) followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred at 23° C. until the evolution of gas ceased (~2 h) and the solvent was evaporated in vacuo leaving a slightly yellow oil; 0.63 g, 95%, ir (neat) νmax : 2100 (N3) and 1785 cm-1 (C--O of acyl chloride); 1Hmr (CDCl3) δ: 4.12 (1H, m, H-1), 3.6 (1H, m, H-3) and 3.1-2.1 ppm (4H, H-2, H-4).
Reaction SMILES: [NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]#[N:21])=[CH:15][C:3]=1[C:4]([O:6]CC(CC)CCCC)=O.[CH3:22][NH2:23]>C[O-].[Na+]>[NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]#[N:21])=[CH:15][C:3]=1[C:4]([NH:23][CH3:22])=[O:6]
Reactant: CCCCC(CC)COC(=O)c1cc(C#N)cc(C)c1N
Reactant: CN
Agent: C[O-]
Agent: [Na+]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Yield: 124.9 %

Procedure:
The above-described method (Example 3) was repeated to stir 2-ethylhexyl 2-amino-5-cyano-3-methylbenzoate (1.00 g, 3.09 mmol) with methylamine (3.60 g, 46.3 mmol, 40% in methanol) and one drop of sodium methoxide (30% in methanol) at room temperature for 18 hours. The entire reaction batch was vacuum distilled and 2-amino-5-cyano-N,3-dimethylbenzamide (730 mg, 91.4% of theory, 73.1 area % LC) was obtained as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)([OH:22])=[O:21].[OH-].[Na+].CC(O)=O>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][C:13](=[CH:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([C:20]([OH:22])=[O:21])[CH:24]=1)[C:12]2=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCOc2ccc(OCc3ccccc3)cc21
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(C=C2COc3ccc(OCc4ccccc4)cc3C2=O)c1
Temperature: 25 °C
Reaction time: 216 h
Yield: 102.9 %

Procedure:
A mixture of 6-benzyloxy-4-chromanone from Step 1 (5.68 g, 20 mmol), 3-carboxybenzaldehyde (30 g, 20 mmol), and 5N NaOH (10 ml, 50 mmol) in MeOH (200 ml) was stirred at r.t. for 9 days. The mixture was diluted with H2O (500 ml), acidified with HOAc to pH 5.6, filtered and air dried to give 7.95 g (98%) of the title compound.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][N:13]1[C:18]2=[CH:19][NH:20][C:21]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])=[C:17]2[C:16](=[O:30])[N:15]([CH3:31])[C:14]1=[O:32].[C:33]([O:37][CH3:38])(=[O:36])[CH:34]=[CH2:35]>C(#N)C>[C:25]([C:24]1[CH:23]=[C:22]([C:21]2[N:20]([CH2:35][CH2:34][C:33]([O:37][CH3:38])=[O:36])[CH:19]=[C:18]3[C:17]=2[C:16](=[O:30])[N:15]([CH3:31])[C:14](=[O:32])[N:13]3[CH3:12])[CH:29]=[CH:28][CH:27]=1)#[N:26]
Reactant: C=CC(=O)OC
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)CCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
DBU (0.656 mL, 4.35 mmol) was added to a solution of 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9 Step 4) (1.22 g, 4.35 mmol) and methyl acrylate (0.392 mL, 4.35 mmol) in acetonitrile (15 mL). The mixture was stirred at room temperature for 4 days. Further portions of methyl acrylate (0.392 mL, 4.35 mmol) and DBU (0.656 mL, 4.35 mmol) were added as required to allow the reaction to run to completion. The reaction was quenched with saturated NH4Cl(aq) and extracted with DCM (2×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-100% EtOAc/hexane afforded a crude material which was triturated with DCM/diethyl ether/hexane to afford the title compound.
Reaction SMILES: [I:1][C:2]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:6](=[S:12])[NH:5][C:4](=[O:13])[CH:3]=1.[CH:14](N(C(C)C)CC)(C)C.IC>CC#N>[I:1][C:2]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:6]([S:12][CH3:14])=[N:5][C:4](=[O:13])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COCCn1c(I)cc(=O)[nH]c1=S
Solvent: CI
Solvent: CC#N
Product: COCCn1c(I)cc(=O)nc1SC
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
To a stirring solution of 6-iodo-1-(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (9.00 g, 28.83 mmol) in MeCN (200 mL) was added diisopropylethylamine (5.0 mL, 28.83 mmol) and iodomethane (9.0 mL, 144.17 mmol). The reaction mixture was stirred at room temperature for 18 hours, and concentrated in vacuo. The residue was partitioned portioned between CH2Cl2 (200 mL) and 1N aqueous HCl (100 mL). The layers were separated and the organic layer was washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by hot trituration with CH2Cl2/heptane to give the title compound (4.05 g, 43%) as a cream colored solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[F:20])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:32][C:31]([F:33])([F:34])[C:29]1[CH:30]=[C:25]([CH:26]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=1)[CH2:24][N:8]([C:5]1[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)[CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=1[F:20]
Reactant: Fc1ccc(C(F)(F)F)cc1CNc1ncc(Br)cn1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
(5-Bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (2.10 g) is dissolved in N,N-dimethylformamide (10 ml) and thereto is added sodium hydride (62.7%) (345 mg) under ice-cooling and the mixture is stirred for 30 minutes, and thereto is added 1-bromomethyl-3,5-bis-trifluoromethyl-benzene (2.76 g) and the mixture is stirred at room temperature for 45 minutes. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (3.30 g). MS (m/z): 576/578 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[C:9]#[CH:10])=[CH:4][CH:3]=1.[N:18]([CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[N+:19]=[N-:20].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>O.C(O)(C)(C)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:9]2[N:20]=[N:19][N:18]([CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:10]=2)[NH:11][S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])=[CH:6][CH:7]=1
Reactant: C#C[C@@H](NS(=O)C(C)(C)C)c1ccc(Br)cc1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)S(=O)N[C@@H](c1ccc(Br)cc1)c1cn(C[Si](C)(C)C)nn1
Reaction time: 24 h

Procedure:
To a solution of 1.5 g (4.8 mmol) N-[(1R)-1-(4-bromophenyl)prop-2-ynyl]-2-methylpropane-2-sulfinamide in 10 mL water and 10 mL t-butanol was added 0.62 g (azidomethyl)(trimethyl)silane, 0.48 mL (0.48 mmol) 1.0M aqueous ascorbic acid solution, and 0.05 mL (0.05 mmol) 1.0M solution of aqueous copper (II) sulfate pentahydrate. After 24 h at room temperature, the reaction mixture was quenched with water, extracted three times with ethyl acetate, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 25-100% EtOAc:hexane) afforded N-((S)-(4-bromophenyl){1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-2-methylpropane-2-sulfinamide. 1H NMR (CDCl3, 400 MHz) 7.51-7.47 (m, 2H); 7.35-7.30 (m, 2H); 7.06 (s, 1H); 5.68 (d, 1H, J=2.65 Hz); 4.58 (d, 1H, J=2.48 Hz); 3.81 (d, 2H, J=3.84 Hz); 1.24 (s, 9H); 0.12 (s, 9H). ES-MS [M+1]+=444.94.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]2[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[NH:13][C:12]([CH3:19])=[C:11]2[C:20]#[N:21])[CH:6]=[CH:7][C:8]=1F)#[N:2].O.[NH2:23][NH2:24]>C(O)CCC>[NH2:2][C:1]1[C:3]2[C:8](=[CH:7][CH:6]=[C:5]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[NH:13][C:12]([CH3:19])=[C:11]3[C:20]#[N:21])[CH:4]=2)[NH:24][N:23]=1
Reactant: NN
Reactant: CC1=C(C#N)C(c2ccc(F)c(C#N)c2)C(C#N)=C(C)N1
Solvent: O
Solvent: CCCCO
Product: CC1=C(C#N)C(c2ccc3[nH]nc(N)c3c2)C(C#N)=C(C)N1
Temperature: 80 °C
Reaction time: 5 h
Yield: 56.6 %

Procedure:
A mixture of 9.5 g (34.1 mmol) 4-(3-cyano-4-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile (Example 1A) and 10 g (312 mmol) hydrazine hydrate in n-butyl alcohol (75 ml) was stirred at 80° C. for 5 h. The mixture was cooled and concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (5.6 g, 57% of th.) as a pale yellow solid.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:36]12[C:50](=[O:51])[NH:49][C:48](=[O:52])[C:46]31[C:47]1[C:38](=[CH:39][CH:40]=[CH:41][C:42]=1[CH2:43][CH2:44][CH2:45]3)[C:37]2=O.C([O:56]C(N=NC(OCC)=O)=O)C>C1COCC1>[O:52]=[C:48]1[N:49]([CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:50](=[O:51])[CH:36]2[CH2:37][C:38]3[CH2:39][CH2:40][CH:41]=[C:42]4[C:47]=3[C:46]12[C:45](=[O:56])[CH:44]=[CH:43]4
Reactant: O=C1NC(=O)C23CCCc4cccc(c42)C(=O)C13
Reactant: O=C(C=Cc1cccnc1)NCCCCO
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCN1C(=O)C2CC3=C4C(=CCC3)C=CC(=O)C42C1=O

Procedure:
Batch size: 4.4 g (20.0 mmol) N-(4-hydroxy-butyl)-3-pyridin-3-yl-acrylamide, 5.2 g (19.8 mmol) triphenylphosphine, 4.8 g (19.9 mmol) 7,8-dihydroacenaphthen-2(6H)-on-1,8a-dicarboximide and 3.5 g (20.0 mmol) azodicarboxylic acid diethyl ester in 65 ml THF.