Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:6]=[C:5]([NH2:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][O:17]P(O)(O)=O)[C@@H:13]([OH:22])[C@H:12]3[OH:23])[C:3]=2[N:2]=1.[NH2:24][C@H:25]([C:36]([OH:38])=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1.CO.CC(C)=O>O>[C@@H:11]1([N:10]2[C:3]3[N:2]=[CH:1][N:6]=[C:5]([NH2:7])[C:4]=3[N:8]=[CH:9]2)[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:22])[C@H:12]1[OH:23].[NH2:24][C@H:25]([C:36]([OH:38])=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
1 mol adenosine-5'-monophosphoric acid is dissolved in 5 parts water. Separately, 2 mols tryptophane are dissolved in 5 parts water. Thereafter, the solution of the amino acid is poured into 9 parts of a 2:1 mixture of methanol and acetone. To this mixture the solution of the nucleotide is slowly added. A. precipitate forms. This precipitate is filtered off and dried at 60°C. Then the precipitate is suspended in water. To the suspension the exact amount of NaOH is added to neutralize the free carboxylic groups of the tryptophane. The precipitate dissolves. The solution is evaporated under reduced pressure, and a white crystalline powder is obtained, which consists of adenosine-5'-monophosphoric acid-(Na-tryptophanate)2.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)=[O:5].[NH2:24][CH:25]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:26][OH:27]>>[OH:27][CH2:26][CH:25]([NH:24][C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)=[O:5])[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCC(N)CO
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1F
Product: CCCCC(CO)Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc2c(c1)OCO2
Yield: 77.8 %

Procedure:
2-[1-(1-Hydroxymethyl)pentylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (203 mg) was prepared from 2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (200 mg) and 2-amino-1-hexanol (221 mg) in a similar manner to that of Example 1(1) as yellow crystals. mp 112-115° C.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])(C)C.O.O.[F-].[K+]>>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])#[CH:5]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)ccc1O
Agent: [F-]
Agent: [K+]
Solvent: O
Product: C#Cc1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 5-[(trimethylsilyl)ethynyl]-2-hydroxybenzoate (100 g, 0.57 mol) and potassium fluoride dihydrate (150 g, 1.59 mol) in DNW (600 ml) was stirred for 4 h at room temperature. The solution was extracted with ether (3×400 ml) and the combined ether extracts were washed with 1 M HCI (2×200 MI) and water (2×100 ml). The ether layer was dried with Na2SO4 and evaporated to dryness. Yield 66.5 g (93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][C:35]([NH2:37])=[O:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([CH2:34][C:35]([NH2:37])=[O:36])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: NC(=O)CS(=O)(=O)c1ccccc1Br
Product: NC(=O)CS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-((2-bromophenyl)sulfonyl)acetamide. MS (ESI): mass calcd. for C18H15FN4O3S, 386.41; m/z found, 387.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.55 (d, J=1.4, 2H), 8.15 (dd, J=7.9, 1.2, 1H), 7.80-7.72 (m, 1H), 7.69-7.61 (m, 1H), 7.59-7.53 (m, 1H), 7.43 (dd, J=7.5, 1.3, 1H), 7.39-7.30 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH2:13]([O:20][C:21]1[CH:48]=[C:47]([O:49][CH2:50][CH2:51]Br)[CH:46]=[CH:45][C:22]=1[C:23]([NH:25][C:26]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.CC(C)=O>[CH2:13]([O:20][C:21]1[CH:48]=[C:47]([O:49][CH2:50][CH2:51][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:46]=[CH:45][C:22]=1[C:23]([NH:25][C:26]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OCCBr)cc1OCc1ccccc1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OCCN2CCOCC2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Potassium carbonate (0.065 g) and morpholine (0.041 mL) were added to an acetone (3.0 mL) solution of tert-butyl 2-(2-(benzyloxy)-4-(2-bromoethoxy)benzamido)-4-phenylbenzoate (0.094 g), followed by heating to reflux for 45 minutes. The reaction mixture was cooled to room temperature, and potassium carbonate (0.022 g) and morpholine (0.014 mL) were added thereto, followed by heating to reflux for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then water, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-91% chloroform/methanol] to obtain 0.059 g of tert-butyl 2-(2-(benzyloxy)-4-(2-(morpholin-4-yl)ethoxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][NH:7][CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH:10](O)[CH2:9]1.[OH-].[NH4+].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O1CCOCC1>[CH3:6][NH:7][CH:8]1[CH:9]=[CH:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][CH2:14]1
Reactant: CNC1CCc2ccccc2C(O)C1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CNC1C=Cc2ccccc2CC1
Yield: 50.3 %

Procedure:
50 ml of 18 N sulfuric acid were added over 30 minutes to a refluxing mixture of 50 g of 7-methylamino-5-hydroxy-6,7,8,9-tetrahydro [5H] benzocycloheptene and 500 ml of dioxane and the mixture was refluxed for an hour and then was cooled. The pH was adjusted to 10 with concentrated ammonium hydroxide solution and the mixture was saturated with ammonium sulfate and was extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried and evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 95-5-2 methylene chloride-methanol-triethylamine mixture yielded 22.8 g of 7-methylamino-6,7-dihydro [5H] benzocycloheptene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:11][OH:12])[CH2:9][OH:10])[CH:5]=[N:6][CH:7]=1.CO[C:15](OC)([CH3:17])[CH3:16].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:8]2[CH2:11][O:12][C:15]([CH3:17])([CH3:16])[O:10][CH2:9]2)[CH:3]=1
Reactant: COC(C)(C)OC
Reactant: OCC(CO)c1cncc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC1(C)OCC(c2cncc(Br)c2)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a solution of 2-(5-bromopyridin-3-yl)propane-1,3-diol (0.12 g, 0.51 mmol) in DCM was added 2,2-dimethoxypropane (0.107 g, 1.03 mmol) and a catalytic amount of p-TSA. The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched by the addition of sat. NaHCO3 solution and the organic layer washed successively with water and brine. The organic layer was concentrated to provide the 3-bromo-5-(2,2-dimethyl-1,3-dioxan-5-yl)pyridine (0.1 g, 71.4%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.53 (m, 2H), 8.17 (t, 2H, J=2 Hz), 4.00-3.92 (m, 4H), 3.07-3.02 (m, 1H), 1.47 (s, 3H), 1.38 (s, 3H).
Reaction SMILES: O[C:2]1[C:3](C)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(OC1C(C)=C(C=CC=1)C(O)=O)(=O)C.[Cl:26][C:27]1[C:28]([CH3:34])=[C:29](O)[CH:30]=[CH:31][CH:32]=1.C(Cl)C1C=CC=CC=1>>[CH2:5]([O:7][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([Cl:26])[C:28]=1[CH3:34])[C:4]1[CH:3]=[CH:2][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: Cc1c(O)cccc1Cl
Agent: CC(=O)Oc1cccc(C(=O)O)c1C
Solvent: ClCc1ccccc1
Product: Cc1c(Cl)cccc1OCc1ccccc1

Procedure:
The invention relates to a process for the preparation of 3-hydroxy-2-methylbenzoic acid and 3-acetoxy-2-methylbenzoic acid, which comprises reacting 3-chloro-2-methylphenol (3) with benzyl chloride to give 2-benzyloxy-6-chlorotoluene (4) subjecting this to a Grignard reaction with magnesium to give (3-benzyloxy-2-methylphenyl)magnesium chloride (5) reacting this with CO2 to give 3-benzyloxy-2-methylbenzoic acid (6) hydrogenating this or its alkali metal salts in the presence of a hydrogenation catalyst to give 3-hydroxy-2-methylbenzoic acid (2) and optionally acetylating this to give 3-acetoxy-2-methylbenzoic acid.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([O:20][Si](C(C)(C)C)(C)C)[CH3:19])[CH:13]=2)[C:7](=[O:28])[C:6]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[NH:46][C:45](=[O:47])[O:44][N:43]=2)=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>O1CCCC1>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:20])[CH3:19])[CH:13]=2)[C:7](=[O:28])[C:6]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[NH:46][C:45](=[O:47])[O:44][N:43]=2)=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2cccc(C(C)O[Si](C)(C)C(C)(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2cccc(C(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 62.8 %

Procedure:
To a solution of 6-butyl-3-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (1.70 g) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1.0 g), and the mixture was stirred at 50° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.88 g, 63%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)c1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2,6-dimethylbenzoic acid (20 g) in conc. sulfuric acid (100 ml) was dropwise added under ice-cooling a mixture of 70% nitric acid and conc. sulfuric acid (21.6 ml), which was prepared by dropwise adding conc. sulfuric acid (10.8 ml) to 70% nitric acid (15.1 ml) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature. Ice-water was added to the reaction mixture, and the resulting precipitates were filtered off. The filtrate was concentrated, and the residue was purified by flash chromatography (dichloromethane:methanol=20:1 including 1% acetic acid) to give 2,6-dimethyl-3-nitrobenzoic acid (7.0 g) as a colorless crystal.
Reaction SMILES: [OH:1][C:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=1)([CH3:22])[C:3]([N:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[OH:1][C:2]([C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)([CH3:22])[C:3]([N:5]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:4]
Reactant: COc1ccc(N(C(=O)C(C)(O)c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(O)(C(=O)N(c1ccc(O)cc1)c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 0 °C
Yield: 77.8 %

Procedure:
2-hydroxy-N,N,2-tris(4-methoxyphenyl)propanamide (0.60 g, 1.47 mmol) was dissolved in 30 mL of anhydrous methylene chloride in a dry 250 mL round-bottomed flask fitted with a stirring bar, anitrogen inlet and rubber stopper. BBr3 solution (6.00 mL of 1 M CH2Cl2 solution, 6.00 mmol) was added dropwise with stirring at 0° C. The reaction solution was stirred at room temperature overnight. The reaction was quenched by adding 20 mL of water and extracted with EtOAc (3×30 mL). The EtOAc layers were separated and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 2-hydroxy-N,N,2-tri(4-hydroxyphenyl)propanamide (11k), 0.42 g, 77.8% yield.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][N:13]=[C:12](Cl)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+].[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][NH:46][C:45](=[O:49])[CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([NH:8][C:9]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:46]2[CH:47]=[CH:48][C:43]([O:42][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:44][C:45]2=[O:49])[CH:11]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1ccnc(Cl)c1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Product: O=C(NCc1ccccc1)c1ccnc(-n2ccc(OCc3ccccc3)cc2=O)c1
Temperature: 110 °C
Yield: 53.3 %

Procedure:
A mixture of N-benzyl-2-chloroisonicotinamide (1.00 g, 4.06 mmol), copper iodide(I) (0.12 g, 0.61 mmol), 8-hydroxyquinoline (0.09 g, 0.61 mmol), potassium carbonate (0.84 g, 6.09 mmol), 4-(benzyloxy)pyridin-2(1H)-one (0.82 g, 4.06 mmol) in N,N-dimethylormamide (20 mL) was heated to 110° C. for 16 hours under nitrogen atmosphere and concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with water (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography eluting with 60-75% ethyl acetate in petroleum ether to give 4-benzyloxy-2-oxo-2H-[1,2′]bipyridinyl-4′-carboxylic acid benzylamide as colorless solid (0.89 g, 53%): mp 158-161° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.60 (d, J=5.0 Hz, 1H), 8.19 (s, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.74 (d, J=5.0 Hz, 1H), 7.42-7.26 (m, 11H), 6.16-6.13 (m, 1H) 5.95 (d, J=2.3 Hz, 1H), 5.02 (s, 2H), 4.58 (d, J=5.6 Hz, 2H); MS (ES+) m/z 412.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([NH:28][S:29]([C:32]1[S:33][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:36]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[S:33][C:34]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=3)[CH:22]=2)=[CH:35][CH:36]=1)(=[O:30])=[O:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1cc(-c2cccc(Cl)c2)nc(-n2cnc(I)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
5-{1-[4-(3-Chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 4-(3-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.72) (0.68 g, 1.5 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.62 g, 1.8 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.4 g), which was subsequently deprotected.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:14][C:13]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:12][N:5]2[C:6](=[O:11])[C:7]=1[N+:8]([O-:10])=[O:9].[NH3:23]>C(O)C>[NH2:23][C:2]1[N:3]=[C:4]2[S:14][C:13]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:12][N:5]2[C:6](=[O:11])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: N
Reactant: O=c1c([N+](=O)[O-])c(Cl)nc2sc(CCC3CCCCC3)nn12
Solvent: CCO
Product: Nc1nc2sc(CCC3CCCCC3)nn2c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
In 100 ml of ethanol was suspended 9.59 g of 7-chloro-2-(2-cyclohexylethyl)-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one, and 7 ml of concentrated aqueous ammonia was added thereto at room temperature while stirring. The stirring was continued for 5.5 hours. The precipitate formed was collected by filtration and washed successively with ethanol and diethyl ether to obtain 7.05 g of 7-amino-2-(2-cyclohexylethyl)-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as a pale yellow crystal.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][O:23][C:22]2=[O:31])[CH2:17][CH2:16]1>>[CH3:12][CH:11]([NH:10][C:8]([C:5]1[CH:6]=[N:7][C:2]([N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH2:24][O:23][C:22]3=[O:31])[CH2:19][CH2:20]2)=[CH:3][CH:4]=1)=[O:9])[CH3:13]
Reactant: CC(C)NC(=O)c1ccc(Cl)nc1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Product: CC(C)NC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)nc1

Procedure:
The title compound was prepared from the product of step (i) (0.4 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.5 g) using the method of example 115 step (ii). Yield 0.22 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]([O:14]C)=O.O.[NH2:17][NH2:18]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]([NH:17][NH2:18])=[O:14]
Reactant: NN
Reactant: COC(=O)c1ncnc2ccc(Br)cc12
Solvent: O
Solvent: CO
Product: NNC(=O)c1ncnc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 961 mg methyl 6-bromoquinazoline-4-carboxylate (compound in Production Example 413), 0.9 mL hydrazine monohydrate and 70 mL methanol was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration. The filtrate was evaporated to give additional crystals. The title compound, 838 mg in total, was obtained as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].[CH3:13][NH:14][NH2:15]>CCOCC>[F:1][C:2]([F:12])([F:11])[C:3]1[N:14]([CH3:13])[N:15]=[C:5]([OH:6])[CH:4]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CCOCC
Product: Cn1nc(O)cc1C(F)(F)F
Temperature: 24 °C
Yield: 25.3 %

Procedure:
A flask was charged with 6 kg of ether and 6164.2 g (33.5 mol) of ethyl 4,4,4-trifluoroacetoacetate. With stirring 1542.4 g (33.5 mol) methylhydrazine was added. The temperature was maintained at about 24° C. during the addition. After one additional hour of stirring the reaction was complete. Solvent was stripped to remove most of the ether and the residue was then slurried in 12 1 of chloroform with vigorous stirring. To the slurry was added 50 ml of concentrated sulfuric acid and the mixture was stirred overnight. An additional 100 ml of sulfuric acid was added and the slurry was washed once with 3 1 of water and 5 times with 3 1 of 10% sodium bicarbonate to remove the 5-hydroxy isomer and twice with 3 1 of water. The aqueous layers and undissolved crystals were twice extracted sequentially with 4 1 of chloroform. Chloroform was stripped on a rotary evaporator at 40° C. under vacuum to yield 1405.9 g (25.3% yield) of a solid, m.p. 130°-131° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Br.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:38]([O:42][CH2:43][CH3:44])(=[O:41])[CH:39]=[CH2:40]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1/[CH:40]=[CH:39]/[C:38]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: C=CC(=O)OCC
Reactant: Nc1cnccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C=C/c1ccncc1N
Temperature: 105 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
3-Amino-4-bromopyridine (1.440 ml, 8.32 mmol), palladium (ii) acetate (0.195 g, 0.869 mmol), and tri(o-tolyl)phosphine (0.302 g, 0.992 mmol) were suspended in a mixture of triethylamine (5.0 ml, 35.9 mmol) and acetonitrile (5 mL) in a microwave vial under argon. Ethyl acrylate (1.1 ml, 10.12 mmol) was added and the cap sealed. It was heated in an oil bath to 105° C. After 2 hours the vial was opened and the reaction mixture partitioned between water (100 mL), saturated ammonium chloride (50 mL) and ethyl acetate (200 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (dichloromethane to ethyl acetate gradient) gave the desired (E)-ethyl 3-(3-aminopyridin-4-yl)acrylate (0.462 g, 2.404 mmol, 28.9% yield).
Reaction SMILES: [C:1]([O:6]C)(=O)[C@@H:2]([CH3:4])[OH:3].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C[O-].[Na+].CO>>[N:8]1([C:1](=[O:6])[C@H:2]([OH:3])[CH3:4])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: C1COCCN1
Reactant: COC(=O)[C@@H](C)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)C(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To (R)-methyl lactate (24.42 g, 0.23 mol) were added morphline (21.46 g, 0.25 mol) and sodium methoxide in methanol (14%, 9.04 g, 0.02 mol) and the mixture was stirred for 3 hours at 50° C. After removal of the solvent in vacuo, the residue was subjected to azeotropic distillation three times with toluene to give the subject compound (quant.).