Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][N:26]([CH2:28][C:29]4([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][N:26]([CH2:28][C:29]4([OH:35])[CH2:34][CH2:33][N:32]([CH3:38])[CH2:31][CH2:30]4)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CN(CC2(O)CCNCC2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1CCC(O)(CN2CC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
A mixture of 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-piperidinol (0.035 g, 0.000074 mol) and formaldehyde (0.006 mL, 37% in water, 0.000082 mol) in dichloroethane (4 mL) was stirred at room temperature under an atmosphere of nitrogen for one hr. Sodium triacetoxyborohydride (0.022 g, 0.000104 mol) was added into the mixture and stirred at ambient temperature under an atmosphere of nitrogen for eighteen hours. Molecular sieves (0.05 g, 3A, 4-8 mesh) and additional formaldehyde (0.006 mL, 37% in water, 0.000082 mol) was added and the reaction mixture was stirred at room temperature for eighteen hours. The solvent was removed under reduced pressure, and the residue was purified by RP-HPLC (Hypersil HS C18, 8 μm, 250×21.1 mm; 5%-100% over 25 min with 0.1 M ammonium acetate, 21 mL/min) to yield 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-1-methyl-4-piperidinol (0.020 g, 0.000041 mol).
Reaction SMILES: [CH2:1]([C@H:8]([NH:18][C:19](=[O:44])[CH:20]([NH:27][C:28](=[O:43])[CH:29](C(=O)C(C)(C)C)[CH2:30]C1C=CC=CC=1)[CH2:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1)[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:45]([OH:47])[CH3:46]>[Pd]>[CH2:1]([C@H:8]([NH:18][C:19](=[O:44])[C@@H:20]([NH:27][C:28](=[O:43])[C@@H:29]([CH2:46][C:45](=[O:47])[C:11]([CH3:14])([CH3:12])[CH3:10])[CH2:30][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1)[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:15])[CH3:16])[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[C@@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)C(Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1)C(=O)C(C)(C)C)C(C)C
Reactant: CCO
Agent: [Pd]
Product: CC[C@@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1)C(C)C

Procedure:
120 mg of N-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]-α-(α-pivaloylhydrocinnamamido)imidazole-4-propionamide in 10 ml of ethanol were hydrogenated at room temperature for 2 hours in the presence of 20 mg of palladium-on-carbon. Thereafter, the catalyst was filtered off and the solvent was evaporated under reduced pressure, to obtain (S)-N-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropylhexyl]-α-[(R)-α-(3,3-dimethyl- 2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide as a foam. MS: 617 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F-].[Cs+].[N+](C1C=C(S(O[CH2:26][C@H:27]2[O:29][CH2:28]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C=O)C>[O:29]1[CH2:28][C@H:27]1[CH2:26][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Oc1cccc2[nH]ccc12
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
4-Hydroxyindole (3.0 g) was dissolved in DMF (10 ml) under nitrogen atmosphere and the solution was cooled to 0° C. Cesium fluoride (10.12 g) was added thereto and the mixture was stirred for 1 hour. Then (S)-glycidyl m-nitrobenzenesulfonate (5.84 g, 99.3% e.e.) was added thereto and the mixture was stirred for 30 hours at the same temperature. After the reaction, water was added to the mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, condensed and the residue was subjected to silica gel chromatography (hexane/isopropyl alcohol; 20:1) to give 4.01 g of (S)-4-(2,3-epoxypropoxy)indole (yield 94.1%, optical purity 99.2% e.e.) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[B:16]([O:25]C(C)C)([O:21]C(C)C)[O:17]C(C)C.[ClH:29]>C1COCC1>[ClH:29].[CH3:9][N:8]([CH3:10])[C:5]1[N:4]=[CH:3][C:2]([O:17][B:16]([OH:25])[OH:21])=[CH:7][N:6]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN(C)c1ncc(Br)cn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)c1ncc(OB(O)O)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-bromo-2-dimethylaminopyrimidine (2.0 g, 9.9 mmol: Bull. Chem. Soc. Jpn., 72, 2523 (1999)) dissolved in THF (25 ml) was added 1.56 M of n-butyl lithium (hexane solution, 7.0 ml, 10.9 mmol) under cooling with a dry ice-acetone bath. After stirring the mixture for 40 minutes, a solution of triisopropyl borate (3.5 ml, 0.15 ml) dissolved in THF (6 ml) was added to the reaction mixture. The temperature of the mixture was raised to room temperature, hydrochloric acid was added to the mixture, and then the solvent was removed. The residue was triturated by methanol-diethyl ether to give 2-dimethylamino-5-pyrimidinylboric acid hydrochloride (2.26 g).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([OH:11])[C:7]([F:12])=[CH:6][C:3]=1[CH:4]=[O:5].Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[F:10][C:9]1[C:2]([F:1])=[C:3]([CH:4]=[O:5])[CH:6]=[C:7]([F:12])[C:8]=1[O:11][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1
Reactant: O=Cc1cc(F)c(O)c(F)c1F
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(Oc2c(F)cc(C=O)c(F)c2F)nc1
Yield: 57.8 %

Procedure:
Using a method similar to Example 710, Part 2, using 2,3,5-trifluoro-4-hydroxy-benzaldehyde (1.00 g, 5.64 mmol), 6-chloronicotinonitrile (782 mg, 5.64 mmol) and K2CO3 (1.17 g, 8.47 mmol) gives 6-(2,3,6-trifluoro-4-formyl-phenoxy)-nicotinonitrile (907 mg) contaminated with 6-chloronicotinonitrile starting material. Dissolve this mixture in MeOH (15 ml) and treat with isoamylamine (194 mg, 2.23 mmol). After stirring for two hours, add NaBH4 (105 mg, 2.79 mmol) and stir for an additional hour. Purification as described in Example 710, Step 4, gives 6-{2,3,6-trifluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinonitrile (383 mg) as a colorless oil.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][O:10][C:9]([CH3:14])([CH3:13])[CH2:8]1)(=O)=O.[Br-:15].[Li+]>CC(C)=O>[Br:15][CH2:6][CH:7]1[CH2:12][CH2:11][O:10][C:9]([CH3:14])([CH3:13])[CH2:8]1
Reactant: CC1(C)CC(COS(C)(=O)=O)CCO1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC1(C)CC(CBr)CCO1
Yield: 88 %

Procedure:
A mixture of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl methanesulfonate (1.5 g) and anhydrous lithium bromide (2.72 g) in acetone (40 mL) was refluxed under nitrogen for 4 h. The reaction was allowed to cool and the solvent was evaporated. The residue was treated with saturated sodium bicarbonate solution and was extracted with DCM (×3). The combined organics were washed with dilute brine, dried by passing through a hydrophobic frit and evaporated to give the title compound as a brown oil (1.23 g).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])[N:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH3:8])[C:3]1=[O:9]
Reactant: Cn1cccc(O)c1=O
Solvent: CO
Product: CN1CCCC(O)C1=O
Temperature: 50 °C
Reaction time: 48 h
Yield: 95.2 %

Procedure:
A mixture of 3-hydroxy-1-methyl-1H-pyridin-2-one (11.5 g, 91.91 mmol) and Ru/Al2O3 (2.5 g) in methanol (120 mL) was stirred under hydrogen (10 bar) in a 250-mL pressure reactor for 48 hr at 50° C. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound (11.3 g, 90%) as a brown oil: 1H NMR (400 MHz, DMSO delta 3.85-3.82 (m, 1H), 3.28-3.18 (m, 2H), 2.79 (s, 3H), 1.98-1.92 (m, 1H), 1.87-1.81 (m, 1H), 1.75-1.69 (m, 1H), 1.64-1.55 (m, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[C:11]2[C:6]([C:7]([F:22])=[CH:8][CH:9]=[C:10]2C)=[N:5]1)[CH2:2][CH3:3].B(Br)(Br)Br.C1CCCCC=1>>[F:22][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[NH:5][N:4]([CH2:1][CH2:2][CH3:3])[CH:12]2[C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1
Reactant: CCCn1nc2c(F)ccc(C)c2c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCN1Nc2c(F)cccc2C1c1ccc(O)cc1
Yield: 10.5 %

Procedure:
Prepared according to Method D step C from 2-propyl-7-fluoro-3-(4-methoxyphenyl)-methyl-2H-indazole (0.006 g, 0.021 mmol), boron tribromide (0.05 mL, 0.5 mmol) and 0.2 mL of cyclohexene to give the product (0.0006 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C)/[CH:15]=[N:16]/[N:17]=[CH:18]/N(C)C>C1(C)C=CC=CC=1>[N:16]1[N:17]=[CH:18][N:12]([CH:9]2[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]2)[CH:15]=1
Reactant: CN(C)/C=N/N=C/N(C)C
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(n2cnnc2)CC1
Yield: 75.3 %

Procedure:
To a stirred solution of ethyl-4-amino-piperidine carboxylate (5 g, 29 mmol) in toluene (100 mL) was added N,N-dimethylformamide azine (8.2 g) and catalytic amount of p-tolunesulfonic acid (0.3 g) and the resulting mixture was refluxed overnight. The mixture was cooled and washed with water, and the aqueous layer was evaporated and the residue was treated with dichloromethane (100 mL). The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified on silica flash column eluting with 4% MeOH, 0.5% NH4OH in dichloromethane to give the desired ethyl 4-(4H-1,2,4-triazol-4-yl)piperidine-1-carboxylate (4.9 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22](O)=[O:23])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:37]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[NH2:37][C:22]([C:21]1[CH:20]=[C:19]([S:16]([N:14]2[C:13]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:12][C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15]2)(=[O:17])=[O:18])[CH:27]=[CH:26][CH:25]=1)=[O:23]
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)O)c2)c1)C(=O)OC(C)(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(N)=O)c2)c1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution (5 mL) of 3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoic acid (205 mg) in N,N-dimethylformamide were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (125 mg) and 1-hydroxy-1H-benzotriazole ammonium salt (100 mg) at room temperature. The mixture was stirred at the same temperature for 1 hr, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1→1:4) to give the title compound as a colorless oil (yield 193 mg, 94%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].O=[C:28](N1C=CN=C1)[N:29]1C=CN=[CH:30]1.CNC>ClCCl.O>[CH3:28][N:29]([CH3:30])[C:22]([C:21]1[CH:25]=[CH:26][C:18]([N:16]2[CH:15]=[C:12]3[C:11]([CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:7])[CH2:14][CH2:13]3)=[N:17]2)=[CH:19][CH:20]=1)=[O:24]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(=O)O)cc3)nc2CC1
Agent: CNC
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(-n2cc3c(n2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[6-{[(1,1-dimethylethyl)oxy]carbonyl}-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzoic acid (may be prepared as described in Description 23) (185 mg, 0.52 mmol) in dichloromethane (10 ml) was added 1,1′-(oxomethanediyl)bis-1H-imidazole (168 mg, 1.04 mmol) and the reaction stirred at room temperature, under argon, overnight. Dimethylamine (93 mg, 2.07 mmol) was added and stirring continued, under argon, at room temperature for 4 hours. The resulting crude mixture was diluted with water, and extracted with dichloromethane (×2). The combined organic fractions were washed with water (×1), dried over magnesium sulphate and solvent evaporated in vacuo to afford the title compound (D41). MS (ES+) m/e 385 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[I-].[Na+].CN(C)P(N(C)C)(N(C)C)=O>O.C(O)C.O>[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCc2ccccc2)cc1

Procedure:
A mixture of 8.25 g. of ethyl p-aminobenzoate, 5.06 g. of 7-phenylheptylchloride, 3.6 g. of sodium iodide and 25 ml. of hexamethylphosphoramide is heated in an oil bath at 110° C. for 20 hours. The mixture is chilled, diluted with 30 ml. of ethanol-water (1:1) and with water to give crystals, m.p. 65°-67° C. Recrystallization from ethanol gives white crystals, m.p. 66.5°-68° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:9]([O:8][C:6]([C:4]1[CH:5]=[N:1][N:2]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1H-Pyrazole-4-carboxylic acid, ethyl ester [CAS Reg. No. 37622-90-5] (1.52 g) was dissolved in dry DMF (25 mL) and cooled to 0° C. under argon. To the mixture was added sodium hydride (651 mg, 60% in mineral oil) and the mixture was allowed to stir at 0° C. for 30 minutes. Benzyl bromide (2.23 g, 1.55 mL) was added over a period of 15 minutes and stirring was continued again for 1 hour at 0° C. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. Toluene was added and the removed by evaporation to remove some residual water. The residue was purified by flash chromatography (50 g silica gel, gradient of ethyl acetate in heptane (10% to 40%) to give the desired material as a light yellow liquid (2.36 g). MS (m/e)=231.1 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19]>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][C:7]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1cccnc1-c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(-c2ncccc2C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-bromophenyl)-3-(trifluoromethyl)-pyridine (0.93 mmol) in H2SO4 (4 mL) cautiously add fuming HNO3 (2 ml). Stir the mixture 30 minutes at room temperature. Pour the mixture onto ice-water (20 mL) and collect the precipitate. Dissolve the precipitate in EtOAc and neutralize with saturated NaHCO3, dry over Na2SO4, concentrate under vacuum to obtain 2-(4-bromo-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C.[Br:25][C:26]1[C:27](Cl)=[N:28][C:29]([Cl:32])=[N:30][CH:31]=1.CO>CN1C(=O)CCC1.C(Cl)Cl.O>[Br:25][C:26]1[C:27]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[N:28][C:29]([Cl:32])=[N:30][CH:31]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1Nc1nc(Cl)ncc1Br
Temperature: 120 °C

Procedure:
To a solution of tert-butyl 2-aminophenylcarbamate (2 g, 9.6 mol) in NMP (15 mL), DIPEA (3.1 g, 24 mmol) and 5-bromo-2,4-dichloropyrimidine (2.78 g, 14.4 mmol) were added and heated to 120° C. for 1 h. TLC showed completion of starting material (TLC system: 5% methanol in DCM (Rf): 0.6). The reaction mixture was diluted with water (50 mL). The obtained solid was filtered, washed with water (35 mL) and dried to obtain tert-butyl 2-(5-bromo-2-chloropyrimidin-4-ylamino)phenylcarbamate as a pale yellow solid. Yield: (2.2 g, 62%). MS: m/z 399.1 (ES+, M+H).
Reaction SMILES: P(Cl)(Cl)Cl.C(NCCC)CC.CCCCCC.[CH2:18]=[C:19]([CH2:31][CH:32]([C:34]([O:36]C)=[O:35])[CH3:33])[C:20]([O:22]CC(CC)CCCC)=[O:21]>O>[CH2:33]=[C:32]([CH2:31][CH:19]([CH3:18])[C:20]([OH:22])=[O:21])[C:34]([OH:36])=[O:35]
Reactant: C=C(CC(C)C(=O)OC)C(=O)OCC(CC)CCCC
Solvent: ClP(Cl)Cl
Solvent: CCCCCC
Solvent: O
Product: C=C(CC(C)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus trichloride (6.85 g.) is added dropwise and continuously to a stirred solution containing 30.4 g. of di-n-propylamine dissolved in 100 ml. of hexane at 10° C. After complete addition, the reaction mixture is allowed to stir 1 hour at room temperature. Sufficient water (75 ml.) is then added to dissolve the amine salt formed, and the organic layer is separated. The organic layer is washed once with 75 ml. of water. Methyl methacrylate (1000 g.) and 2 g. of the methyl ether of hydroquinone are added to the organic layer and heated to 65° C. To this stirred solution, 276 g. of 2-ethylhexyl acrylate is added dropwise over 8 to 10 hours. After a total of 24 hours at 65° C., the hexane and unconverted esters are removed via distillation. The residue is distilled to give 200 g. of 2-ethylhexyl 2-methylene-4-carbomethoxypentanoate, b.p. 120°-125° C./0.1 mm, nD25 = 1.4452-1.4463 and 164 g. of di-2-ethylhexyl glutarate, b.p. 150°-155° C./0.1 mm, nD25 = 1.4513. The 2-ethylhexyl 2-methylene-4-carbomethoxypentanoate is saponified to give 2-methylene-4-methylglutaric acid having a melting point of 106° to 108° C. and an acid number of 727. This product is further identified by elemental analysis and nmr spectroscopy.
Reaction SMILES: C([Sn]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)(CCCC)CCCC)CCC.Br[C:21]1[O:22][CH:23]=[CH:24][C:25]=1[Br:26]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[Br:26][C:25]1[CH:24]=[CH:23][O:22][C:21]=1[C:18]1[CH:19]=[CH:14][N:15]=[CH:16][CH:17]=1
Reactant: Brc1ccoc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1ccoc1-c1ccncc1
Temperature: 100 °C
Yield: 24.7 %

Procedure:
A solution of tributylstannylpyridine (8.0 g, 21.7 mmol) and 2,3-dibromofuran (5.9 g, 26.1 mmol) in dry toluene (200 ml) was treated with bis(triphenylphosphine)palladium (II) chloride (1.5 g, 2.2 mmol) and heated at 100° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to afford the title compound (1.2 g, 25%); 1H NMR (CDCl3) 8.66 (2H, d, J 11 Hz), 7.84 (2H, d, J 11 Hz), 7.50 (1H, d, J 3 Hz), 6.60 (1H, d, J 3 Hz).
Reaction SMILES: Br[C:2]1[C:3]2[S:17][CH:16]=[CH:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:7]=1.C(OC(=O)[NH:24][C:25]1[S:26][C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:28][N:29]=1)(C)(C)C>CC(N(C)C)=O.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>[NH2:24][C:25]1[S:26][C:27]([C:2]2[C:3]3[S:17][CH:16]=[CH:15][C:4]=3[N:5]=[C:6]([C:8]3[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=3)[N:7]=2)=[CH:28][N:29]=1
Reactant: Oc1cccc(-c2nc(Br)c3sccc3n2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: Nc1ncc(-c2nc(-c3cccc(O)c3)nc3ccsc23)s1
Temperature: 150 °C
Yield: 21.9 %

Procedure:
A suspension of 3-(4-bromo-thieno[3,2-d]pyrimidin-2-yl)-phenol (128 mg, 0.42 mmol), (5-tributylstannyl-thiazol-2-yl)-carbamic acid tert-butyl ester (306 mg, 0.63 mmol), and Pd(PPh3)4 (25 mg, 0.021 mmol) in anhydrous DMA (4 ml) was heated in a microwave at 150° C. for 15 mins. The reaction was absorbed onto silica and purified using 10% methanol in ethyl acetate as the eluent to give the title compound as an off-white solid (30 mg, 22%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[CH:4]([CH3:9])[CH:5]([CH3:8])[CH2:6][CH:7]=1.CC1C(=O)C(C)CCC=1C.CC1CCC(=O)C(C)=C1C.C(=O)=O.[H][H]>[Pd]>[CH3:9][C:4]1[C:5]([CH3:8])=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[OH:10]
Reactant: [H][H]
Reactant: CC1=CCC(C)C(C)C1=O
Agent: [Pd]
Agent: CC1=C(C)C(=O)C(C)CC1
Agent: CC1=C(C)C(C)CCC1=O
Product: Cc1ccc(C)c(O)c1C
Yield: 95 %

Procedure:
Dehydrogenation may be carried out in an inert solvent. It is advantageous however to dehydrogenate the 2,5,6-trimethyl-2-cyclohexen-1-one or 2,3,6-trimethyl-2-cyclohexen-1-one in the gas phase, for example by passing it as a gas at the dehydrogenation temperature over a palladium/silica gel catalyst. In gas-phase dehydrogenation the trimethyl-2-cyclohexen-1-one is preferably passed over the catalyst in admixture with an extraneous gas such as nitrogen, steam, carbon dioxide and particularly hydrogen; generally a ratio by volume of extraneous gas to gaseous trimethyl-2-cyclohexen-1-one of from about 1:2 to 5:1 is chosen. Temperatures of from 200° to 400° C., preferably from 250° to 350° C., are usually used in gas-phase dehydrogenation. The time that the trimethyl-2-cyclohexen-1-one is in contact with the catalyst is generally from half to fifty, preferably from two to ten seconds. The 2,3,6-trimethylphenol is obtained in a more than 95% yield in gas-phase dehydrogenation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]3[N:10]([CH2:11][CH2:12][CH2:13]3)[CH:9]=2)=[CH:4][CH:3]=1.[O:22]=[C:23](Cl)[O:24][C:25](Cl)(Cl)Cl.CO>C1COCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]3[N:10]([C:9]=2[C:23]([O:24][CH3:25])=[O:22])[CH2:11][CH2:12][CH2:13]3)=[CH:6][CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Clc1ccc(-c2cn3c(c2-c2ccccc2)CCC3)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccc(Cl)cc2)c(-c2ccccc2)c2n1CCC2
Reaction time: 8 h

Procedure:
6-(4-Chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example 17 a, 1.5 g, 5.1 mmol), dissolved in THF (10 ml), is treated with 1 drop of triethylamine (about 50 mg). A solution of diphosgene (0.5 g, 2.5 mmol), dissolved in THF (5 ml), is added dropwise to this solution at RT and it is stirred for 8 h. Methanol (abs., 3 ml) is then added, and the mixture is stirred at RT for a further 12 h. The solvent is completely removed in vacuo (45° C.). The resinous residue is dissolved in CHCl3 (20 ml) and washed twice with water (20 ml). After the removal of the solvent in vacuo, a residue which is recrystallized from a little diisopropyl ether is obtained from the CHCl3 phase dried using Na2SO4 sicc.