Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[N:23]O)[C:14]=2[CH:13]=[CH:12][CH:11]=1>[Ni].C(O)C.O1CCCC1>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([NH2:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cccnc2[nH]1
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1c2ccccc2-c2c(-c3nc4cccnc4[nH]3)cccc21
Yield: 85.4 %

Procedure:
Carry out the procedure as in Example 6, starting from 1.30 g of 4-(3H-imidazo[4,5-b]pyridin-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the preceding stage, and 2.45 mg of Raney Nickel in 65 ml of ethanol and 65 ml of tetrahydrofuran for 5 hours at 60° C. under a hydrogen pressure of 1 bar. After purification by making a paste in diisopropyl ether, we obtain 1.06 g of 4-(3H-imidazo[4,5-b]pyridin-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a white powder, with the following characteristics:
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:55])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][CH2:39][C:40]([N:42]3[CH2:46][CH2:45][CH2:44][C@H:43]3[C:47](=[O:53])[NH:48][CH:49]3[CH2:52][CH2:51][CH2:50]3)=[O:41])[C:35]3[C:30](=[CH:31][C:32]([CH3:54])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:55])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][CH2:39][C:40]([N:42]3[CH2:46][CH2:45][CH2:44][C@H:43]3[C:47](=[O:53])[NH:48][CH:49]3[CH2:52][CH2:51][CH2:50]3)=[O:41])[C:35]3[C:30](=[CH:31][C:32]([CH3:54])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.5 g 4-[(S)-4-tert-Butoxycarbonyl-2-({4-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-naphthalene-2-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester in 10 ml dichloromethane were added 1.1 g TFA. After 3 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. The crude product was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). Yield: 970 mg MS (ES+): m/e=708.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:23][CH2:22][CH2:21][O:20][CH3:19])[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(C(=O)NCc2nccnc2Cl)CC1
Reactant: COCCN
Product: COCCNC1CCC(C(=O)NCc2nccnc2Cl)CC1
Yield: 94.2 %

Procedure:
Using the procedure described in example 7 step 7a N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclo-hexanecarboxamide (1 g) and 2-methoxyethanamine (0.281 g) gave N-((3-chloropyrazin-2-yl)methyl)-4-(2-methoxyethylamino)cyclohexanecarboxamide (1.15 g, mixture of cis and trans).
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[N:18]=[CH: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]([N:34]1[CH2:37][C:36]([F:39])([F:38])[CH2:35]1)(=[O:33])=[O:32]>>[F:39][C:36]1([F:38])[CH2:35][N:34]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:37]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CC(F)(F)C1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CC(F)(F)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-3,3-difluoroazetidine. MS (ESI): mass calcd. for C19H15F3N4O2S, 420.09; m/z found, 421.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37-8.26 (m, 2H), 8.14-8.07 (m, 1H), 8.02-7.95 (m, 1H), 7.77-7.69 (m, 1H), 7.66-7.57 (m, 1H), 7.48-7.40 (m, 1H), 7.35-7.24 (m, 2H), 4.02-3.92 (m, 4H).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:7]=1[NH2:20]>C(O)(=O)C.C(Cl)Cl>[Cl:5][C:6]1[C:7]2[N:20]=[N:1][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Cc1ccccc1Nc1ncnc(Cl)c1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccccc1-n1nnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
Sodium nitrite (0.323 g, 4.69 mmol) was added to 6-chloro-N4-o-tolylpyrimidine-4,5-diamine (Intermediate AP5)(1 g, 4.26 mmol) in acetic acid (50% Aq) (25 mL)and DCM (25 mL) at room temperature. The resulting solution was stirred at room temperature for 15 minutes. The reaction mixture was separated and the organic phase was washed with water (10 mL), dried (MgSO4) and evaporated to give crude 7-chloro-3-o-tolyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (0.980 g, 94%) that was used without further purification.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.C1COCC1.[Cl:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][CH:22]=1.S(=O)(=O)(O)O>C(OCC)C>[CH2:9]([O:8][C:1](=[O:7])[C:2]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:16])[CH:22]=1)=[O:4])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Clc1cccc([Mg]Br)c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cccc(Cl)c1
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
Diethyl oxalate (4.4 g, 30.2 mmol) was dissolved in dry ethyl ether (30 mL) and freshly distilled THF (30 mL) and cooled to −78° C. with stirring, under a nitrogen atmosphere. Then added 3-chlorophenylmagnesium bromide (0.5 M in THF, 72.5 mL, 36.2 mmol) dropwise, via an addition funnel, while keeping the temperature between −75 to −78° C. The addition took approximately 90 minutes. After 3 hours, the reaction was quenched by the dropwise addition of 2N sulfuric acid (50 mL, 91 mmol) at −78° C. and upon completion of the addition, the mixture was allowed to return to room temperature. The mixture was extracted with ethyl ether (3×) and the combined ether extracts were washed with brine (2×), dried over magnesium sulfate, filtered, evaporated in vacuo and vacuum-dried to yield ethyl-(3-chlorophenyl)(oxo)acetate (6.5 g, HPLC RT=3.46 min, Method A; LCMS m/z=213).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>CN(C)C1C=CN=CC=1.O1CCCC1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[NH:32][C:33]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:34]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cc1ccc(F)c(N=C=O)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 1.45 g of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine, 1.86 mL of triethylamine and 162 mg of 4-dimethlaminopyridine in 150 mL of tetrahydrofuran at 20° C. is added 1 g of 1-fluoro-2-isocyanato-4-methylbenzene. The reaction is stirred for 3 hours 30 minutes at 60° C., and then concentrated to dryness under reduced pressure. The residue is taken up in a mixture of water and dichloromethane. The organic phase is washed with 1N HCl solution and then dried over magnesium sulfate and concentrated to dryness under reduced pressure. 2.13 g of a white powder of 1-(2-fluoro-5-methylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea are obtained, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]3)=[N:21][CH:22]=2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 56.1 %

Procedure:
Following general procedure F, (S)-tert-butyl 1-(5-(6-bromo-3-propionylquinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (80 mg, 0.14 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.17 mmol) to afford the desired product (50 mg, 54%) as an orange solid: ESI MS m/z 636 [C33H35Cl2H5O4+H]+
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1/[CH:4]=[C:16](/[C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=1)\[C:17]#[N:18]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1c(F)cccc1F
Product: COc1ccc(/C(C#N)=C/c2c(F)cccc2F)cc1OC
Yield: 59.5 %

Procedure:
2,6-Difluorobenzaldehyde (284 mg) and 3,4-dimethoxybenzyl cyanide (354 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (358 mg, yield: 40%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Mg]Br.[CH3:8][N:9]([CH3:32])[C:10]1(C#N)[CH2:15][CH2:14][CH:13]([CH:16]([O:24][CH:25]([O:27][CH2:28][CH3:29])[CH3:26])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:11]1.O.[Cl-].[NH4+]>O1CCCC1>[CH2:28]([O:27][CH:25]([O:24][CH:16]([CH:13]1[CH2:14][CH2:15][C:10]([N:9]([CH3:32])[CH3:8])([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:12]1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:26])[CH3:29]
Reactant: Br[Mg]c1cccs1
Reactant: CCOC(C)OC(Cc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)OC(Cc1ccccc1)C1CCC(c2cccs2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 1 M solution of 2-thienylmagnesium bromide in tetrahydrofuran (9.25 ml, 9.25 mmol) was added dropwise to a solution of 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanecarbonitrile (1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml), while cooling with ice and under an argon atmosphere. The mixture was stirred at room temperature for 48 h and water and saturated ammonium chloride solution (10 ml of each) were then added. The phases were separated and the aqueous phase was extracted with diethyl ether (3×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:8]([OH:9])[CH2:7][O:6][CH2:5][O:4]1)[CH3:2].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C[O-].[Na+].C1(C)C=CC=CC=1>[CH2:10]([O:9][C@H:8]1[CH2:7][O:6][CH2:5][O:4][C@H:3]1[CH2:1][CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC[C@@H]1OCOC[C@@H]1O
Reactant: ClCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC[C@@H]1OCOC[C@@H]1OCc1ccccc1
Yield: 63.6 %

Procedure:
The procedure of Example XVIII was followed using 4.5 g of cis-4-ethyl-5-hydroxy-1,3-dioxane and 8.1 g of a methanolic solution 25% in sodium methylate, and 4.3 g of benzyl chloride in 180 ml of dry toluene. The reaction product was distilled under reduced pressure to give in free fractions 4.8 g of cis-5-benzyloxy-4-ethyl-1,3-dioxane; bp 96°-100°/0.01 mm; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]3([C:32]4[C:33]([O:38][CH2:39][CH3:40])=[N:34][CH:35]=[CH:36][CH:37]=4)[C:27]4[C:22](=[CH:23][C:24]([F:30])=[C:25]([C:28]#[N:29])[CH:26]=4)[NH:21][C:20]3=[O:31])=[O:17])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[CH3:41][O:42][C:43]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:44]=1[S:51](Cl)(=[O:53])=[O:52]>CN(C)C=O>[CH3:3][N:4]1[CH2:5][CH2:6][CH:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]3([C:32]4[C:33]([O:38][CH2:39][CH3:40])=[N:34][CH:35]=[CH:36][CH:37]=4)[C:27]4[C:22](=[CH:23][C:24]([F:30])=[C:25]([C:28]#[N:29])[CH:26]=4)[N:21]([S:51]([C:44]4[CH:45]=[CH:46][C:47]([O:49][CH3:50])=[CH:48][C:43]=4[O:42][CH3:41])(=[O:53])=[O:52])[C:20]3=[O:31])=[O:17])[CH2:12][CH2:11]2)[CH2:8][CH2:9]1
Reactant: CCOc1ncccc1C1(OC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)Nc2cc(F)c(C#N)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ncccc1C1(OC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2cc(F)c(C#N)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
9.2 mg (0.19 mmol) of sodium hydride (50% dispersion in mineral oil) were added to a solution of 50 mg (0.10 mmol) of 5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate in 2 ml of anhydrous dimethylformamide under a nitrogen atmosphere and while cooling in an ice bath. The mixture was stirred at 0° C. for 10 min and then 29 mg (0.12 mmol) of 2,4-dimethoxyphenylsulfonyl chloride were added, and stirring was continued at room temperature for 30 min. The reaction mixture was poured into ice-water and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by chromatography on silica gel (Redisep cartridge, mobile phase gradient from 0 to 20% methanol in dichloromethane). 34 mg of the title compound were obtained as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].F[C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].C(OCC)(=O)C>CN(C)C=O>[N:1]1([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccccc1F
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 1H-imidazole (0.61 g, 9.0 mmol) in dimethylformamide (8 ml) was added sodium hydride (60% in oil, 0.36 g, 9.0 mmol) and the reaction mixture was stirred at room temperature for 40 min. 2-Fluoro-benzonitrile (0.9 ml, 8.2 mmol) was added and the reaction was stirred at room temperature for 45 min, heated to 60° C. for 45 min and then stirred at room temperature overnight. Ethyl acetate was added and the mixture was washed with water and brine. Drying and solvent evaporation gave 2-imidazol-1-yl-benzonitrile; 1H NMR (CDCl3, 400 MHz) δ 7.86 (bs, 1H), 7.84 (m, 1H), 7.75 (m, 1H), 7.54 (m, 1H), 7.47 (dd, 1H, J=8.1 Hz, J=1 Hz), 7.36 (m, 1H), 7.27 (m, 1H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][CH2:7]Cl)[CH3:4].[S:9]([O-])([O-])(=O)=[S:10].[Na+].[Na+].Cl.[OH-].[Na+]>O>[CH3:2][N:3]([CH3:4])[CH2:5][CH2:6][CH2:7][S:10][S:9][CH2:7][CH2:6][CH2:5][N:3]([CH3:4])[CH3:2]
Reactant: CN(C)CCCCl
Reactant: O=S([O-])([O-])=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCCSSCCCN(C)C
Reaction time: 2 h

Procedure:
In a 300 ml round-bottom flask were charged 31.6 g of N,N-dimethyl-3-chloropropylamine hydrochloride, 34.8 g of sodium thiosulfate and 100 ml of distilled water. The mixture was heated under reflux and stirred for 2 hours and then continuously heated under reflux for further 1 hour after the addition of 22.3 g of 36% hydrochloric acid. Under cooling in an ice bath, 25.3 g of 95% sodium hydroxide was slowly added to adjust pH to the alkaline range, and the mixture was subjected to extraction three times with 30 ml of tetrahydrofuran. Most of the water was removed with potassium hydroxide pellets. The extract was further dehydrated with anhydrous potassium carbonate, and the solvent was removed by distillation and distilled under reduced pressure to give a transparent colorless bis(N,N-dimethyl-3-aminopropyl)disulfide as the precursor of the mercaptoalkylamine desired in an amount of 22.5 g.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>CO.O>[S:12]1[CH:13]=[CH:14][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]1=2
Reactant: CCOC(=O)c1cccc2ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2ccsc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
To a solution of benzo[b]thiophene-7-carboxylic acid ethyl ester (1.0 g, 48 mmol) in methanol (10 mL) and water (10 mL) is added sodium hydroxide (5 g, excess). The solution is stirred at room temperature for 30 min; at which point all the ester has been consumed. The reaction mixture is adjusted to pH 1 by adding 6M HCl solution, and extracted with DCM. The combined organic layers are filtered through a silica plug to afford the title compound as a yellow solid (505.2 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl.O>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1NC(=O)C(C)(C)C
Yield: 93 %

Procedure:
A biphasic solution of o-toluidine (107.2 g, 1.0 mol) in methylene chloride (500 ml) and water (150 ml) containing sodium carbonate (69 g, 0.65 mol) was treated with trimethylacetyl chloride (120.6 g, 1.0 mol). The rate of addition of trimethylacetyl chloride was adjusted so as to maintain the reaction at gentle reflux. After 45 minutes the addition was complete. The organic layer was separated, washed with water, and concentrated in vacuo. The crude N-[(2-methyl)phenyl]-2,2-dimethylpropanamide was slurried in 2% aqueous HCl, filtered and washed with H2O until the filtrate was neutral. After drying in vacuo (50° C., 20 mm), N-[(2-methyl)phenyl]-2,2-dimethylpropanamide (178 g, 0.93 mol) was obtained in 93% yield (m.p. 109°-110° C).
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH:17]=3)[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH+]1C=CC=CC=1.O>CN(C)C=O>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:12]1[CH:11]=[CH:10][C:6]2[C:7](=[O:9])[CH:8]=[C:3]([C:1]3[NH:36][N:35]=[N:34][N:2]=3)[O:4][C:5]=2[CH:13]=1
Reactant: N#Cc1cc(=O)c2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(-c2nnn[nH]2)oc2cc(COc3cccc(OCc4ccc5ccccc5n4)c3)ccc12
Temperature: 100 °C

Procedure:
0.72 g of 2-cyano-7-(3-(quinolin-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran, 0.54 g of sodium azide and 0.96 g pyridinium chloride are combined in 20 ml of dimethylformamide and heated for 3 hours at 100° C. The mixture is poured into water and the precipitate filtered off. This crude product is recrystallized from dimethylformamide to give 5-(7-(3-(quinolin-2-ylmethoxy)-phenoxymethyl)-4-oxo-4H-1-benzopyran-2-yl)tetrazole; m.p. 246° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[Cl:23][C:24]1[CH:34]=[CH:33][C:27]2[S:28][C:29]([CH2:31]Cl)=[CH:30][C:26]=2[CH:25]=1>CC(O)(C)C>[Cl:23][C:24]1[CH:34]=[CH:33][C:27]2[S:28][C:29]([CH2:31][N:15]([CH2:16][C:17]([F:19])([F:18])[F:20])[C:12]3[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:21])([F:22])[F:1])=[CH:14][CH:13]=3)=[CH:30][C:26]=2[CH:25]=1
Reactant: OC(c1ccc(NCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Reactant: ClCc1cc2cc(Cl)ccc2s1
Solvent: CC(C)(C)O
Product: OC(c1ccc(N(Cc2cc3cc(Cl)ccc3s2)CC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 120 °C
Reaction time: 10 h
Yield: 19.8 %

Procedure:
A solution of 100 mg (0.29 mmol) of 1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-ol (example 11.2) in 0.5 mL tBuOH was treated with 115 mg (0.44 mmol) of 5-chloro-2-chloromethyl-benzo[b]thiophene and stirred at 120° C. for 10 hours in a sealed tube. Evaporation of the solvent and column chromatography on silicagel with n-heptane/EtOAc 8:1 yielded 30 mg (19%) of 2-{4-[(5-chloro-benzo[b]thiophen-2-ylmethyl)-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellow oil, MS: 520 ((M-H)−, 1Cl).
Reaction SMILES: [N:1]#[C:2]Br.[C:4]([NH:9][NH2:10])(=[O:8])[CH2:5][CH2:6][CH3:7]>CO>[CH2:5]([C:4]1[O:8][C:2]([NH2:1])=[N:10][N:9]=1)[CH2:6][CH3:7]
Reactant: CCCC(=O)NN
Reactant: N#CBr
Solvent: CO
Product: CCCc1nnc(N)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.2 %

Procedure:
To a solution of 5.0 g (47.0 mmol) cyanogen bromide in 50 ml of methanol was added dropwise over a period of 30 min a solution of 4.80 g (47.0 mmol) butyric acid hydrazide in 50 ml of methanol. The mixture was then refluxed for 15 min, and then concentrated in vacuo till cristallisation began. The cristals (9 g) were filtered off, taken up in 60 ml of ethanol. Then 5 g of finely powdered potassium carbonate were added and the suspension was stirred for 5 min at room temperature. The resulting orange suspension was filtered, and the filtrate was concentrated in vacuo. The resulting orange powder (5.5 g) was purified by flash chromatography on silicagel with a 80:10:1 mixture of methylene chloride/methanol/28% ammonia as eluent to yield 3.95 g (31.1 mmol, 66%) of 5-propyl-[1,3,4]oxadiazol-2-ylamine as white cristals, MS: m/e=127 (M+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]#[N:8])[S:5][CH:6]=1.[C:9](OC)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[SH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9](=[O:17])[N:8]=2)[S:5][CH:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1csc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1csc(-c2nc(=O)c3ccccc3s2)n1
Yield: 48.9 %

Procedure:
4-Methyl-1,3-thiazole-2-carbonitrile (0.27 g, 2.2 mmol) and methyl thiosalicylate (0.75 g, 4.4 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxed for 6 hrs. After cooling, the precipitates were collected by filtration and recrystallized from ethanol to give the titled compound (0.28 g, 49%) as yellow crystals.