Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]2N=N[N:11]=[C:7]2[C:6]([CH2:12][CH:13]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[Cl:23])[CH3:15])=[C:5]([CH3:24])[N:4]=1.O>C(O)(=O)C.[Zn]>[NH2:2][C:3]1[N:8]=[C:7]([NH2:11])[C:6]([CH2:12][CH:13]=[C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[Cl:23])[CH3:15])=[C:5]([CH3:24])[N:4]=1
Reactant: CC(=CCc1c(C)nc(N)n2nnnc12)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC(=CCc1c(C)nc(N)nc1N)c1cc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 18 h
Yield: 30.9 %

Procedure:
Zinc is activated by treating 2.5 grams (excess) of it with aqueous 10% hydrochloric acid for two minutes. The activated zinc is collected by filtration, washed with water then acetone, and dried in a vacuum oven for one hour. A solution of 1.5 grams (0.004 mole) of 5-amino-7-methyl-8-[3-(2,5-dichlorophenyl)-2-butenyl]tetrazolo[1,5-c]pyrimidine in 35 mL of acetic acid is stirred, and the activated zinc is added portionwise during a 20 minute period. Upon completion of addition, the reaction mixture is warmed to about 80° C. where it is stirred for about 18 hours. After this time, the reaction mixture is stirred with 50 mL of water. The mixture is then extracted with three 30 mL portions of methylene chloride. The combined extracts are washed with two 10 mL portions of an aqueous solution saturated with sodium bicarbonate. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using 15% methanol in methylene chloride as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 0.4 gram of 2,4-diamino-6-methyl-5-[3-(2,5-dichlorophenyl)-2-butenyl]pyrimidine; mp 172°-174° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[S:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:18]1([C:4]2[CH:5]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:7]=[C:2]([C:25]3[CH:26]=[CH:27][S:23][CH:24]=3)[N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(S(=O)(=O)c2cc(-c3ccsc3)nc(N3CCCC3)c2)cc1
Yield: 16.6 %

Procedure:
A mixture of 191 mg (0.5 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 70 mg (0.5 mmole) 3-thiophen-boronic acid, 55 mg sodium carbonate and 18 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 18 hours in 5 ml 1,2-dimethoxyethane and 0.25 ml water. The solvent is removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with water, dried over magnesiumsulfate and concentrated in vacuo. Flash chromatography (silicagel, ethyl acetate/hexane 1/1) of the residue yields 32 mg (16%) pure 4-(2-pyrrolidine-1-yl-6-thiophen-3-yl-pyridine-4-sulfonyl)-phenylamine as a light brown solid mp.: 260° C.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]2[O:6][C:7]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:35]([O:1][C:2]1[CH:34]=[CH:33][C:5]2[O:6][C:7]([C:10]([N:12]3[CH2:13][CH2:14][N:15]([CH:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[CH2:16][CH2:17]3)=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(C1=COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)OC=C(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2
Reaction time: 1 h
Yield: 92 %

Procedure:
Dissolve 0.5 g (1.07 mmol) of the compound obtained in Example 1 at 0° C. in 0.255 ml (2.7 mmol) of acetic anhydride under an inert atmosphere. Add 2 volumes of pyridine (0.5 10 ml) and continue stirring while returning to room temperature for a period of 1 h 30. Neutralise with a saturated sodium hydrogen carbonate solution. After extraction with ether (2×25 ml), the product is purified by chromatography on a silica column (eluant:ethyl acetate/petroleum ether, 20:80) and obtained in pure form as a solid in a yield of 92%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1.O>N1C=CC=CC=1>[CH:28]1([C:31]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][C:9]([C:12]([N:14]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[CH2:18][N:17]5[CH:25]=[CH:26][CH:27]=[C:16]5[CH2:15]4)=[O:13])=[CH:8][CH:7]=3)=[N:2]2)=[O:32])[CH2:30][CH2:29]1
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(c1ccc(-c2ccn(C(=O)C3CC3)n2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
To a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]-benzodiazepin-10-yl)-methanone (1.0 g) in dry pyridine (10 ml) was added cyclopropanecarbonyl chloride (0.44 g). After stirring at room temperature for 18 hours the reaction mixture was poured into water and the precipitate was collected by filtration. The crude product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. This solution was filtered through a short column of hydrous sodium magnesium silicate, eluting with several additional volumes of dichloromethane. The eluant was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.88 g) was obtained as a crystalline solid, m.p. 197-199° C.
Reaction SMILES: CN(C)C=O.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[N:12]1[C:17]2[CH:18]=[CH:19][S:20]C=2C(=O)[NH:14][CH:13]=1.O>ClC(Cl)C>[Cl:11][C:6]1[C:7]2[S:20][CH:19]=[CH:18][C:17]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1[nH]cnc2ccsc12
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ncnc2ccsc12
Temperature: 25 °C
Yield: 75.7 %

Procedure:
Dimethyl formamide (6.6 mL, 85.4 mmol) in 50 mL of dichloroethane was cooled to 0° C. and oxalyl chloride (62 mL, 124 mmol, 2M in dichloromethane) was added slowly over several minutes forming a white gel. 3H-thieno[3,2-d]pyrimidin-4-one (5.90 g, 38.8 mmol) was added and the reaction mixture was heated to reflux. After 2.5 hours the mixture was cooled to room temperature and poured into water. The product was extracted into dichloromethane (3×100 mL), dried over sodium sulfate, and concentrated in vacuo to afford 5.01 g (76%) of 4-chloro-thieno[3,2-d]pyrimidine. 1H NMR (400 MHz, DMSO) d 8.99 (s, 1H), 8.55 (d, 1H), 7.71 (d, 1H). LC-MS: 171 (MH+); HPLC RT: 2.85 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:44]([O:48][CH3:49])(=[O:47])[CH:45]=[CH2:46]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:46]=[CH:45][C:44]([O:48][CH3:49])=[O:47])[CH3:9]
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1ccccc1[C@@H](C)OC[C@H]1CO1
Temperature: 25 °C

Procedure:
(2R)-2-[[(1R)-1-(2-Bromophenyl)ethoxy]methyl]oxirane (1.00 g) obtained in Step 1 was dissolved in acetonitrile (10 ml), palladium acetate (II) (45 mg), tri-o-tolylphosphine (63 mg), triethylamine (0.65 ml) and methyl acrylate (0.42 ml) were added, and the mixture was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature, and, after filtration through celite, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (203 mg).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:21]=[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:19]=[CH:18][C:17]=3[NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:42]=[CH:43][CH:44]=3)[CH2:34][S:35][CH2:36][CH2:37][C:38]([O:40]C)=[O:39])=[O:30])=[O:15])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>O>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[CH:21]=[C:20]([N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)[CH:19]=[CH:18][C:17]=3[NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:42]=[CH:43][CH:44]=3)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])=[O:15])=[CH:11][N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3ccccc3)nc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3ccccc3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
Into a 50 mL round-bottom flask was placed methyl 3-((3-((2-((2-phenylpyrimidin-5-yl)carbamoyl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzyl)thio)propanoate (crude product of 1459-084), and a solution of lithium hydroxide (387 mg, 9.21 mmol, 24.98 equiv) in water (2 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of water and adjusted to pH 4-5 with hydrochloric acid (2 N). The resulting solution was extracted with 4×30 mL of ethyl acetate and the organic layers combined, washed with 1×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The resulting mixture was washed with 3×5 mL of ethyl ether. This resulted in 120 mg (55%) of product as a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 12.21 (s, 1H), 10.86-10.97 (d, 2H), 9.21 (s, 2H), 8.36-8.38 (m, 2H), 8.11 (m, 1H), 7.75-7.88 (m, 2H), 7.39-7.52 (m, 6H), 7.24 (m, 1H), 3.84 (s, 2H), 3.23-3.33 (s, 4H), 2.56-2.61 (m, 4H), 1.58-1.67 (d, 6H). MS (ES, m/z): 596 [M+H]+.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].OO.[Cl:9][C:10]1[C:11]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH:27]=[O:28])[CH:21]=2)=[N:12][N:13]([CH3:19])[C:14]=1[O:15][CH:16]([F:18])[F:17].Cl([O-])=[O:30].[Na+].Cl>O.C(#N)C>[C:27]([C:22]1[CH:21]=[C:20]([C:11]2[C:10]([Cl:9])=[C:14]([O:15][CH:16]([F:18])[F:17])[N:13]([CH3:19])[N:12]=2)[CH:25]=[CH:24][C:23]=1[Cl:26])([OH:30])=[O:28]
Reactant: Cn1nc(-c2ccc(Cl)c(C=O)c2)c(Cl)c1OC(F)F
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: O=P([O-])(O)O
Agent: OO
Solvent: CC#N
Solvent: O
Product: Cn1nc(-c2ccc(Cl)c(C(=O)O)c2)c(Cl)c1OC(F)F
Reaction time: 1 h

Procedure:
A solution of 4 g (34 mmol) of sodium dihydrogen phosphate in 40 ml of water and then 12.5 ml of 35% hydrogen peroxide solution were added at 10-15° C. to a solution of 40 g (125 mmol) of 4-chloro-3-(4-chloro-3-formylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 125 ml of acetonitrile. A solution of 18.1 g (200 mmol) of sodium chlorite in 158 ml of water was then added dropwise at 10° C. to the mixture. After stirring for one hour the mixture was acidified to pH 1 with 3N hydrochloric acid. The product then present in suspended form in the reaction mixture was separated off and recrystallized from methanol/water. Yield: 24.5 g.
Reaction SMILES: [NH2:1]N.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C1C=CC=C2C(NC(=O)C=12)=O>CO>[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:1]
Reactant: NN
Reactant: CN1CCNCC1CCCCCCc1cccc2c1C(=O)NC2=O
Solvent: CO
Product: CN1CCNCC1CCCCCCN

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 6-(N-methylpiperazinyl)hexylphthalimide (263 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=C)[CH2:10][CH:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([C:35]5[NH:36][C:37]([CH:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])=[N:38][CH:39]=5)[CH:31]=4)[CH:26]=3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCCC1C1NC(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=CN=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[C:30]([C:35]5[NH:36][C:37]([CH:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:48])[CH3:49])=[N:38][CH:39]=5)[CH:31]=4)[CH:26]=3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C

Procedure:
This compound was made using the same procedure used to make 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS-ESI+: calc'd for C42H49N7O5: 731.38 (M+); Found: 732.81 (M+H+).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:15]([N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][NH:7][CH3:6])[CH2:11]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(CC1CCN(C(c2ccccc2)c2ccccc2)C1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC1CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1-Benzhydryl-pyrrolidin-3-ylmethyl)methyl carbamic acid-tert-butyl ester (0.47 g, 1.67 mmol) was dissolved in dry CH2Cl2 (15 ml) followed by addition of TFA (8 ml). The resulting solution was stirred at r.t. for 2 hrs. The solution was concentrated under reduced pressure. The resulting residue was dissolved in water (12 ml) and pH of the solution was adjusted to 10. The water phase was extracted with CH2Cl2 (100 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product in almost quantitative yield.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=[O:3].[NH2:13]C(N)=O.CN(C)C=O.N>CO.O>[NH:6]1[C:7]2[C:1](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2](=[O:3])[NH:13][C:5]1=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NC(N)=O
Agent: N
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)c2ccccc2[nH]1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
978 g of isatoic acid anhydride were added in portions with stirring at 150° C. to a mixture of 720 g of urea and 1 liter of dimethylformamide and the mixture was then heated at 180° C. until evolution of ammonia ceased. The mixture was cooled and one liter of water was immediately added thereto followed by the addition of one liter of methanol. The warm mixture was stirred for one hour and was then filtered. The product was rinsed with warm water and with methanol and was then added with stirring to 2-3 volumes of warm dimethylformamide. The mixture was filtered and the product was rinsed with methanol to obtain 747 g of quinazoline-2,4-dione.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]Cl.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(=O)([O-])O.[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][NH:19][CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])c(CCl)c1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNCc1cc(C)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 6 h

Procedure:
5.0 g (27 mmol) of 5-methyl-2-nitrobenzyl chloride was dissolved in 100 ml of ethanol. 7.5 g (54 mmol) of glycine ethyl ester hydrochloride and 6.8 g (81 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 70° C. for 6 hours. The solvent was evaporated. After the extraction with ethyl acetate, the extract was washed with 1 N hydrochloric acid. The obtained aqueous layer was made basic with 1 N sodium hydroxide. After the extraction with ethyl acetate, the obtained organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14]([OH:16])=O)=[CH:9][CH:8]=1)(=[O:4])=[O:3].[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[C:29]([CH2:30][NH2:31])=[CH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[N:26]2)[CH:22]=[CH:23][CH:24]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(#N)C.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[C:29]([CH2:30][NH:31][C:14](=[O:16])[CH:13]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:12][CH:11]=3)[CH3:17])=[CH:28][C:27]([C:32]([F:33])([F:34])[F:35])=[N:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(CNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
To a stirred solution of 2-(4-(methylsulfonamidomethyl)phenyl)propanoic acid (37 mg, 0.144 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (44 mg, 0.158 mmol) in acetonitrile were added EDC (41 mg, 0.216 mmol), HOBt (29 mg, 0.216 mmol) and triethylamine (0.05 mL, 0.36 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and filtered. The solvent was removed in vacuo. The crude product was purified by CC. Example compound B5 (62 mg) was obtained in 84% yield.
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([C:30]([OH:47])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:46])([O:39]C3CCCCO3)[CH3:38])[CH3:31])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C.[CH3:48]O>C1COCC1>[OH:39][C:37]([CH3:38])([CH3:46])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][C:30]([C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:14]=[C:15]([OH:17])[CH:16]=[C:11]([OH:10])[CH:12]=2)[CH:29]=[CH:28][CH:27]=1)([O:47][CH3:48])[CH3:31]
Reactant: CO
Reactant: CCOCOc1cc(C=Cc2cccc(C(C)(O)CCCCCC(C)(C)OC3CCCCO3)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COC(C)(CCCCCC(C)(C)O)c1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.2 ml of concentrated sulphuric acid in 3 ml of methanol with 350 mg (0.6 mmol) of 2-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}-8-methyl-8-(tetrahydropyran-2-yloxy)nonan-2-ol in 3 ml of methanol and 3 ml of THF, after purification on a silica column (ethyl acetate 60-heptane 40), white crystals (m=76 mg; Y=32%) are obtained. m.p.=65-75° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]([F:20])([F:19])[C:16](=[O:18])[CH3:17]>CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]([OH:18])([CH3:17])[C:15]([F:20])([F:19])[F:14])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 62.4 %

Procedure:
A 500 mL round-bottomed flask was charged with 1,4-dibromobenzene (30.27 g, 128 mmol, Sigma-Aldrich, St. Louis, Mo.) and 200 mL of ether. After cooling to −78° C., n-BuLi (59.0 mL, 2.5 M in hexanes, 148 mmol) was added. This mixture was stirred for 15 min at −78° C., then 1,1,1-trifluoro-2-propanone (24.2 mL, 257 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. Stirring was continued at −78° C. for 30 min then the mixture was quenched with 100 mL of saturated aqueous NH4Cl. The mixture was extracted with EtOAc (250 mL), dried (MgSO4) and concentrated to give an oil. Purification via column chromatography (330 g of silica, 0 to 30% EtOAc in hexanes) gave 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (21.50 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10]#[N:11])=[C:4]([F:12])[CH:3]=1.[F:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([F:12])[C:5](/[C:9](=[CH:16]/[C:15]2[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:14]=2[F:13])/[C:10]#[N:11])=[C:6]([F:8])[CH:7]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: N#CCc1c(F)cc(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Cl)c1F)c1c(F)cc(Cl)cc1F
Yield: 76.2 %

Procedure:
Step B In a manner similar to the method described in Example 1b, (4-chloro-2,6-difluoro-phenyl)-acetonitrile (1.1 g, 6 mmol) was reacted with 2-fluoro-3-chlorobenzaldehyde (1.2 g, 7 mmol), methanolic solution (25 wt %) of sodium methoxide (1.5 mL, 7 mmol) in methanol (40 mL) at 50° C. for 3 h to give (Z)-2-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile as a white solid (1.5 g, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][O:18][CH3:19])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[CH3:32][N:33]([CH3:44])[C:34](=[O:43])[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([NH2:42])[CH:37]=1>CN(C=O)C.C(Cl)Cl.C(OCC)(=O)C>[CH3:32][N:33]([CH3:44])[C:34]([O:35][C:36]1[CH:37]=[C:38]([NH:42][C:14]([C:11]2([CH2:17][O:18][CH3:19])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH:39]=[CH:40][CH:41]=1)=[O:43]
Reactant: CN(C)C(=O)Oc1cccc(N)c1
Reactant: COCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(methoxymethyl)-piperidine-4-carboxylic acid from step B (718 mg, 2.63 mmol), pyridine (0.84 mL, 10.52 mmol), and DMF (catalytic, 3 drops) in CH2Cl2 (13 mL) was added dropwise oxalyl chloride (0.25 mL, 2.89 mmol, caution: exothermic). After gas evolution subsided, the reaction was stirred at ambient temperature for 30 minutes. 3-Aminophenyl dimethylcarbamate (475 mg, 2.63 mmol) was added in one portion to this solution and stirred for another 30 minutes. The reaction was quenched with saturated aqueous NH4Cl, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. Silica gel chromatography (50% ethyl acetate:hexanes) afforded the title compound (1.03 g, 90% yield for two steps). MS (ES+) [M+NH4]+=453.3