Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21]O)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.O=S(Cl)[Cl:25]>C(Cl)Cl>[Cl:25][CH2:21][C:16]1[C:15]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:13]([F:14])[CH:12]=2)=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3CO)cc2F)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Nc1cnc(-c2ccc(-c3ccccc3CCl)cc2F)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
A mixture of (4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-yl)methanol (1.8 g, 6.1 mmol) and SOCl2 (6 mL) in DCM (20 mL) was stirred at 70° Celsius for 4 hours. The reaction mixture was cooled to rt and concentrated to dryness to give 5-(6′-(chloromethyl)-3-fluorobiphenyl-4-yl)pyrazin-2-amine (1.86 g, 98%). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.04 (s, 1H), 7.96 (m, 1H), 7.66-7.57 (m, 1H), 7.51-7.42 (m, 2H), 7.40-7.30 (m, 3H), 6.89-6.62 (br s, 2H), 4.73 (s, 2H).
Reaction SMILES: [Na+].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([O-:15])=[O:14])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([O:14][C:13](=[O:15])[CH:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:11][CH:10]=1)[CH3:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)OCc2ccccc2)cc1
Temperature: 90 °C
Yield: 86.8 %

Procedure:
To a mixture of 2.28 g of 2-(p-isobutylphenyl)propionic acid sodium salt in 20 ml of dimethylformamide was added 2.52 g of benzyl chloride and the whole was heated at 90° C. for 3 hours. After the reaction was complete, the solvent was removed by distillation under reduced pressure to leave a residue, to which was added water. The resulting mixture was extracted with ether and the extract was dehydrated. The ether was removed by distillation to give an oily product. Distillation of this product under reduced pressure yielded 2.57 g of 2-(p-isobutylphenyl)propionic acid benzyl ester as a colorless oil, boiling at 108°-110° C./0.1 mmHg. Analysis-Calculated for C20H24O2 : C, 81.04; H, 8.16. Found: C, 80.92; H, 8.02.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]([NH:23][NH2:24])=O)[C:17]=3[O:19][CH3:20])[NH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:26](=[NH:30])(OC)[CH3:27].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[NH:23][N:24]=[C:26]([CH3:27])[N:30]=4)[C:17]=3[O:19][CH3:20])[NH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C(=O)NN)ccc2[nH]nc(/C=C/c3cccc(F)c3)c12
Reactant: COC(C)=N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1c(-c2nc(C)n[nH]2)ccc2[nH]nc(/C=C/c3cccc(F)c3)c12
Temperature: 150 °C
Reaction time: 17.5 h
Yield: 5.8 %

Procedure:
To a suspension of 19 mg of 3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic acid hydrazide in 4 mL of ethanol were added 50 mg of O-methyl acetimidate hydrochloride and 0.19 mL of triethylamine, and stirred in a sealed tube at 150° C. for 17.5 hours. The reaction solution was allowed to cool to room temperature, the solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography, and further purified and separated by LC-MS, to afford 1.17 mg of the title compound as a yellow amorphous.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1.[NH2:12][OH:13]>CO>[OH:13][N:12]=[C:10]([C:5]1[C:4]2[CH:3]=[CH:2][NH:1][C:9]=2[CH:8]=[CH:7][CH:6]=1)[NH2:11]
Reactant: NO
Reactant: N#Cc1cccc2[nH]ccc12
Solvent: CO
Product: NC(=NO)c1cccc2[nH]ccc12

Procedure:
In a 50 ml reaction vessel, to a solution of 1H-indole-4-carbonitrile (5.00 g) in CH3OH (100 ml) was added hydroxylamine (50% aqueous solution) at room temperature, followed by refluxing for 15 hours (completion of the reaction was confirmed by TLC). The reaction solution was concentrated under reduced pressure, and azeotroped with toluene three times. The obtained solid was washed with IPE. N′-Hydroxy-1H-indole-4-carboximidamide (6.12 g) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[S:4][C:3]1=S.C1(C)C=CC(S(OC)(=O)=O)=CC=1.C1(OC)C=CC=CC=1.[CH2:35]([N:42]1[C:46](=[O:47])[CH2:45][S:44][C:43]1=[N:48][C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][C:56]=1[NH:57][CH2:58][CH3:59])[C:52]#[N:53])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC#N>[CH2:35]([N:42]1[C:46](=[O:47])[C:45](=[C:3]2[N:2]([CH3:1])[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:5]([CH3:13])[S:4]2)[S:44][C:43]1=[N:48][C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][C:56]=1[NH:57][CH2:58][CH3:59])[C:52]#[N:53])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1ccccc1
Reactant: Cc1sc(=S)n(C)c1-c1ccccc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC#N
Solvent: COc1ccccc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2SC(C)=C(c3ccccc3)N2C)C(=O)N1Cc1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
To an 8 mL vial was added 3,5-dimethyl-4-phenyl-3H-thiazole-2-thione (100 mg, 0.45 mmol), methyl p-toluenesulfonate (126 mg, 0.68 mmol) and anhydrous anisole (0.5 mL). The reaction was heated to 120° C. and stirred for 3 h. The cooled reaction mixture was diluted with anhydrous MeCN (3 mL) and then treated with 3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-(ethylamino)benzonitrile (50 mg, 0.14 mmol) and TEA (70 μL, 0.50 mmol). The reaction mixture was warmed to 80° C. and the resulting solution was allowed to stir for 16 h. The product mixture was concentrated under reduced pressure and chromatographed (silica gel, 1:1 EtOAc/Hex) to yield the title product (48.3 mg, 64%) as a yellow solid. 1H-NMR (CDCl3): δ 7.40 (5H, m) 7.33 (2H, m), 7.25 (3H, m), 7.23 (2H, m), 6.46 (1H, d), 5.15 (2H, s), 4.28 (1H, m), 3.46 (3H, s), 2.99 (2H, m), 2.28 (3H, s), 1.01 (3H, t); MS(ESI): 538 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.BrC[C:32]1[CH:37]=[CH:36][C:35]([C:38]([OH:47])([C:43]([F:46])([F:45])[F:44])[C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:32]3[CH:37]=[CH:36][C:35]([C:38]([OH:47])([C:43]([F:44])([F:46])[F:45])[C:39]([F:42])([F:40])[F:41])=[CH:34][CH:33]=3)[CH2:12][CH2:13]2)=[O:7])=[CH:21][CH:22]=1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 8 h
Yield: 54.4 %

Procedure:
tert-Butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (4.98 mmol, 1.520 g) was dissolved in dichloromethane and trifluoroacetic acid added. The reaction was left overnight and then treated to SCX purification. The intermediate amine was combined with 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.98 mmol, 1.678 g) and potassium carbonate (4.98 mmol, 0.688 g) in acetonitrile (30 mL) and stirred overnight. The reaction was concentrated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. Purification by SCX column chromatography and silica chromatography (eluting with ethyl acetate) gave the title compound (1.25 g).
Reaction SMILES: [Cl:1][C:2]1([Cl:14])[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[H-].[Na+]>O1CCCC1>[Cl:14][C:2]1([Cl:1])[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:3]1=[O:13]
Reactant: O=C1Nc2ccccc2CCC1(Cl)Cl
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(Cl)(Cl)CCc2ccccc21
Reaction time: 2 h

Procedure:
A solution of 3,3-dichloro-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (1.0 g, 4.32 mmol) and ethyl bromoacetate (0.51 ml) in of tetrahydrofuran (30 ml) was added dropwise with stirring during 15 minutes to a solution of sodium hydride (4.76 mmol) in tetrahydrofuran (20 ml) at room temperature under a nitrogen atmosphere. Stirring was continued for an additional 2 hours. The solution was quenched by addition of saturated aqueous ammonium chloride and the solvents were removed under reduced pressure. The residue was extracted with ether (3×20 ml), and the combined ether solutions washed with saturated brine (20 ml) and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave 3,3-dichloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one. NMR(CDCl3): δ1.27 (t, 3H); 3.22 (m, 4H); 4.25 (q, 2H); 4.65 (s, 2H), 7.3 (m, 4H).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.Cl.[CH2:13]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH2:19])[CH3:14].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl.O>[CH2:13]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH:19][CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[CH3:14]
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)CCN
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNCc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.2 %

Procedure:
A mixture of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (9.41 g, 27.1 mmol) and β-alanine ethyl ester hydrochloride (5.00 g, 32.5 mmol) in DMF (75 mL) was treated with N,N-diisopropylethylamine (16.5 mL, 94.9 mmol). After stirring at room temperature for 4 h, the cloudy mixture was diluted with CH2Cl2 (100 mL) and H2O. The aqueous layer was extracted with CH2Cl2 (2×150 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent removed in vacuo. Purification by column chromatography (silica gel, CH2Cl2/MeOH/Et3N, 95/4.5/0.5 to 80/19.5/0.5) gave the title compound (1.90 g, 23%) as a tan oil: MS (ESI) m/le 302 (M+H)+.
Reaction SMILES: C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1NC(C1C(N2N=CC=N2)=CC=CN=1)=O.[CH3:32][C@:33]1([NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=2)[CH2:37][CH2:36][CH2:35][C@@H:34]1[NH2:38].[Cl:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:55]([CH:59]=1)[C:56](O)=[O:57]>>[Cl:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:55]([CH:59]=1)[C:56]([NH:38][C@H:34]1[CH2:35][CH2:36][CH2:37][C@:33]1([CH3:32])[NH:39][C:40]1[CH:45]=[N:44][C:43]([C:46]([F:49])([F:47])[F:48])=[CH:42][N:41]=1)=[O:57]
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Reactant: O=C(O)c1cc(Cl)ccc1-n1nccn1
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1cc(Cl)ccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 90 mg, 0.35 mmol) and 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 38a; CAS number 1293284-54-4; 93 mg, 0.42 mmol) except this was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) followed by recrystallisation from diethyl ether/pentane to afford the title compound.
Reaction SMILES: ClC1C=C(N[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15]C(C3CC3)=O)[CH:10]=2)C(=O)N2C(C3C=CC=C(F)C=3)(C)NC(=O)C=12.ClC1C=[C:39]([N:41](CC2C=CC(OC)=CC=2)[C:42]2[CH:47]=[CH:46][N:45]=CN=2)C(=O)N2C3(CCCCC3)N(CC3C=CC(OC)=CC=3)C(=O)C=12.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:39][N:41]1[CH:42]=[C:47]([C:10]2[C:11]([NH2:15])=[N:12][CH:13]=[N:14][CH:9]=2)[CH:46]=[N:45]1
Reactant: COc1ccc(CN(c2ccncn2)c2cc(Cl)c3n(c2=O)C2(CCCCC2)N(Cc2ccc(OC)cc2)C3=O)cc1
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(-c2cncnc2N)cn1
Temperature: 110 °C

Procedure:
To a solution of 5-iodopyrimidin-4-amine (1, 0.5 g, 2.26 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2, 0.56 g, 2.71 mmol) in dioxane/water (15 mL, 9:1.5) in a vial, was added cesium carbonate (1.84 g, 5.66 mmol) and the mixture was degassed with argon for 15 min. To this mixture was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.09 g, 0.11 mmol) and then heated to 110° C. for 16 h. TLC showed consumption of starting material, cooled the reaction mixture to ambient temperature, filtered the mass over celite bed, washed with dichloromethane (30 mL) followed by concentration of filtrate. The crude compound was purified by flash column chromatography eluting with 3% methanol in dichloromethane. The desired fractions were concentrated to dryness to afforded as 5-(1-methylpyrazol-4-yl)pyrimidin-4-amine (3) as off white solid; Yield: 0.2 g, 50%; MS (ESI) m/z 176.08 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.70 (s, 1H), 6.61 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[F:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[N:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=2)=[CH:18][CH:17]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH2:27][C:24]3[CH:25]=[N:26][C:21]([O:20][C:19]4[CH:29]=[CH:30][C:16]([F:15])=[CH:17][CH:18]=4)=[CH:22][CH:23]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: NCc1ccc(Oc2ccc(F)cc2)nc1
Product: O=C1c2ccnc(Cl)c2CN1Cc1ccc(Oc2ccc(F)cc2)nc1
Yield: 54 %

Procedure:
The title compound is prepared in 54% yield (130 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (180 mg, 0.64 mmol, Step-1 of Intermediate-1) and (6-(4-fluorophenoxy)pyridin-3-yl)methanamine (140 mg, 0.64 mmol, Amine-18) in a similar manner to Intermediate-2.
Reaction SMILES: [O:1]=[C:2]([CH2:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].C(C(C)=O)CC.C(OCC)(=O)CCC.[NH2-].[Li+].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]#[N:45])=[CH:34][CH:33]=1>CN(C=O)C>[C:44]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:35]1[CH:34]=[CH:33][C:32]([CH2:31][CH:6]([C:7](=[O:11])[CH2:8][CH2:9][CH3:10])[C:2](=[O:1])[CH2:3][CH2:4][CH3:5])=[CH:37][CH:36]=1)#[N:45]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCC(=O)CC(=O)CCC
Agent: [H-]
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCC(C)=O
Solvent: CN(C)C=O
Solvent: CCCC(=O)OCC
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
15.6 g of 4,6-dioxononane, prepared from methyl propyl ketone and ethyl butyrate in the presence of lithium amide (according to CA 42 : 4129 f), are dissolved in 160 ml of anhydrous DMF. 4 g of 60% NaH are added in portions. When the exothermic effect has subsided, the mixture is cooled to room temperature and a solution of 27.2 g of 4'-bromomethyl-2-cyanobiphenyl, prepared in Example 4, in 90 ml of DMF is introduced dropwise. The mixture is stirred for 30 min at room temperature and then heated at 60° C. for 2 h. It is concentrated under vacuum and the concentrate is taken up in a water/dichloromethane mixture and acidified with a dilute solution of HCl. After decantation, the aqueous phase is extracted twice with dichloromethane. The organic phases are washed with water, dried and then concentrated to give 36.3 g of an oil, which is purified by chromatography twice in succession (eluent: chloroform, then cyclohexane 90%/ethyl acetate 10% respectively) to give a solid identified by NMR as being the enol tautomer melting at 105° C., and an oil corresponding to the diketone tautomeric form.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[NH2:29][C:30]1[CH:31]=[C:32]([S:36]([NH:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[OH:42][CH2:41][C:40]([NH:39][S:36]([C:32]1[CH:31]=[C:30]([NH:29][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:28])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:35]=[CH:34][CH:33]=1)(=[O:38])=[O:37])([CH3:44])[CH3:43]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC(C)(C)CO)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Light yellow solid. MS (ISP) 626.6 [(M−H−]; mp 250° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:8]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:5]2=[N:6][CH:7]=1.[CH2:22]([SH:24])[CH3:23]>>[C:11]([C:9]1[N:8]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2=[N:6][CH:7]=[C:2]([S:24][CH2:22][CH3:23])[CH:3]=[C:4]2[N:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CCS
Reactant: CC(C)(C)c1nc2cc(Br)cnc2n1CC1CCOCC1
Product: CCSc1cnc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step E of Example 32 from 6-bromo-2-tert-butyl-3-(tetrahydro-2H-pyran-4-ylmethyl)-3H-imidazo[4,5-b]pyridine (Step F) and ethanethiol (Wako Pure Chemical Industries, Ltd.).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].[OH-].[Na+]>C(Cl)Cl>[CH2:1]([NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=1[O:15][CH3:14])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: COc1ccc(CN)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNCc1ccc(OC)cc1OC
Yield: 40 %

Procedure:
0.32 ml of allylbromide (3.66 mM) and 0.7 ml of diisopropyl ethylamine (3.99 mM) were added to the reaction solution containing 500 mg of 2,4-dimethoxybenzylamine (3.33 mM) dissolved in methylene chloride with stirring and the solution was left alone at room temperature. After the reaction mixture was neutralized with 10% NaOH solution, the mixture was extracted with chloroform, washed with saturated NaCl solution, dried over MgSO4, filtered, and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 276 mg of allyl-(2,4-dimethoxybenzyl)amine (1b) (yield: 40%).
Reaction SMILES: [CH2:1]([C:9]1[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[C:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:11]2[S:12][CH:13]=[CH:14][C:10]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.[CH3:34][Sn:35](Cl)([CH3:37])[CH3:36].O>O1CCCC1>[CH2:1]([C:9]1[C:17]2[S:18][C:19]([Sn:35]([CH3:37])([CH3:36])[CH3:34])=[CH:20][C:16]=2[C:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:11]2[S:12][C:13]([Sn:35]([CH3:37])([CH3:36])[CH3:34])=[CH:14][C:10]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1c2ccsc2c(CCCCCCCC)c2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCc1c2cc([Sn](C)(C)C)sc2c(CCCCCCCC)c2cc([Sn](C)(C)C)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 4,8-dioctylbenzo[1,2-b:4,5-b′]dithiophene (782 mg, 1.89 mmol) in dry tetrahydrofuran (36 mL) was added n-butyllithium (2.5 M in hexane, 1.66 mL, 4.15 mmol) at −78° C. After 1 hour, trimethyltin chloride (877 mg, 4.40 mmol) was added in one portion. The mixture was stirred at room temperature for 2 hours, poured into water and extracted with ether three times. The organic layer was washed with brine and dried over anhydrous MgSO4. Upon evaporating the solvent, a pale yellow oil was obtained (1.03 g, yield 74%). Upon standing for one week, yellow crystals emerged and were collected (413 mg, yield 29%). 1H NMR (CDCl3, 500 MHz) δ=7.51 (s, 2H), 3.22 (t, J=8.0 Hz, 4H), 1.76-1.89 (m, 4H), 1.45-1.54 (m, 4H), 1.22-1.45 (bs, 16H), 0.90 (t, J=7.0 Hz, 6H), 0.47 (s, 18H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=O)C.O.[NH2:17][NH2:18]>C(O)C>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[C:4]([NH:17][NH2:18])=[O:3]
Reactant: CCOC(=O)c1ccc2ccccc2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc2ccccc2c1
Yield: 48.4 %

Procedure:
To a solution of 2-naphthyl carboxylic acid ethyl ester (2.0 g, 9.99 mmol) in absolute ethanol (30 ml) was added hydrazine hydrate (4.85 ml, 99.9 mmol) and the reaction mixture was heated at reflux temperature for 72 h. The reaction mixture was cooled and the precipitate was filtered off, washed with 96% ethanol (2×10 ml) and diethyl ether (3×10 ml), dried in vacuo at 50° C. which afforded 0.9 g (48%) of naphthalene-2-carboxylic acid hydrazide as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:24]2[CH:23]=[C:22]([OH:25])[CH:21]=[CH:20][C:19]=2[C@@H:18]2[C@H:9]([C@H:10]3[C@@:14]([CH2:16][CH2:17]2)([CH3:15])[C@@H:13]([OH:26])[CH2:12][CH2:11]3)[CH:8]=1)=[O:5])[CH3:2].O1CCCC1.[H][H].C(OC(C[C@H]1C2C=C(O)C=CC=2[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)[C@@H](O)CC3)C1)=O)C>[Pd].C([O-])([O-])=O.[Ca+2].CO>[CH2:1]([O:3][C:4]([CH:6]=[C:7]1[C:24]2[CH:23]=[C:22]([OH:25])[CH:21]=[CH:20][C:19]=2[C@@H:18]2[C@H:9]([C@H:10]3[C@@:14]([CH2:16][CH2:17]2)([CH3:15])[C@@H:13]([OH:26])[CH2:12][CH2:11]3)[CH2:8]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC1=C[C@@H]2[C@H](CC[C@]3(C)[C@@H](O)CC[C@@H]23)c2ccc(O)cc21
Agent: [Pd]
Agent: CCOC(=O)C[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)[C@@H](O)CC[C@@H]23)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C=C1C[C@@H]2[C@H](CC[C@]3(C)[C@@H](O)CC[C@@H]23)c2ccc(O)cc21

Procedure:
20 g. of 6-ethoxycarbonylmethyl-1,3,5(10),6-estratetraene-3,17β-diol is hydrogenated in 280 ml. of tetrahydrofuran and 280 ml. of methanol in the presence of 2 g. of Pd/CaCO3 (10%) until 1 millimole of hydrogen has been absorbed per millimole of substance. The thus-obtained product is 6β-ethoxycarbonylmethyl-1,3,5(10)-estratriene-3,17β-diol as a foamy mass. The same compound is also produced by the analogous hydrogenation of 6-ethoxycarbonylmethylene-1,3,5(10)-estratriene-3,17β-diol. The preparation of 6β-ethoxycarbonylmethyl-1,3,5(10)-estratriene-3,17β-diol can be simplified by hydrolyzing the crude product of the Reformatskii reaction, freeing the thus-obtained hydrolyzate from by-products by fractional filtration over silica gel, and hydrogenating the evolved mixture of 6-ethoxycarbonylmethyl-1,3,-5(10),6-estratetraene-3,17β-diol and 6-ethoxycarbonylmethylene-1,3,5(10)-estratriene-3,17β-diol as indicated above.