Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([OH:19])=[CH:10][C:8]1=[O:9])[CH3:6]>C(O)(=O)C>[CH2:5]([N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:11]([OH:19])=[C:10]([N+:1]([O-:4])=[O:2])[C:8]1=[O:9])[CH3:6]
Reactant: CCn1c(=O)cc(O)c2cc(C)ccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCn1c(=O)c([N+](=O)[O-])c(O)c2cc(C)ccc21

Procedure:
Concentrated nitric acid (2.5 ml; d, 1.42) was added to a suspension of 1-ethyl-4-hydroxy-6-methyl carbostyril. (1.82g; 0.009 mole) in glacial acetic acid (10 ml) and the mixture warmed to 100° C. The solid dissolved and the 3-nitro derivative immediately solidified as a yellow solid. After cooling the solid was filtered, washed well with water and dried in vacuo over P2O5, m.p. 192°-4° C; (Found; C, 58.16; H, 5.02; N, 11.29; C12H12N2O4 requires; C, 58.06; H, 4.87; N, 11.29%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[O:3][CH2:2]1.[F:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:27](=[O:28])[CH2:26][F:25])[C:4]=2[O:3][CH2:2]1
Reactant: c1ccc(Oc2ccccc2NCc2cccc3c2OCO3)cc1
Reactant: O=C(Cl)CF
Solvent: ClCCl
Product: O=C(CF)N(Cc1cccc2c1OCO2)c1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a solution of N-(benzo[1,3]dioxol-4-ylmethyl)-N-(2-phenyloxy-phenyl)amine (0.16 g, 0.50 mmol) dissolved in DCM (2 mL) was added TEA (0.20 g, 2.00 mmol, 0.28 mL). The reaction was cooled to 0° C. and fluoroacetyl chloride (0.10 g, 1.00 mmol, 0.07 mL) was added. The mixture was stirred at room temperature for 1 h. The solvents were removed in vacuo, the residue quenched with water (10 mL), extracted with DCM (2×20 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with DCM (A) and MeOH (B) (1-5% B, 80 g, 4.0 CV, 60 mL/min) to afford 160 mg (84%) of N-(benzo[1,3]dioxol-4-ylmethyl)-2-Fluoro-N-(2-phenyloxy-phenyl)acetamide as a yellow oil. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δ 4.67 (1H, d, J=2 Hz, FCH), 4.83 (1H, d, J=2 Hz, FCH), 4.74 (1H, d, J=14 Hz, ArCH), 5.12 (1H, d, J=14 Hz, ArCH), 5.63 (1H, d, J=1 Hz, OCHO), 5.79 (1H, d, J=1 Hz, OCHO), 6.66-6.88 (6H, m, ArH), 6.96-7.06 (2H, m, ArH), 7.12-7.38 (4H, m, ArH).
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:10][N:9]1[C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=1)=[O:7])#[N:3]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)c1ccc(F)cc1

Procedure:
L14. (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K2 was coupled with 4-fluoro-benzoic acid in analogy to experiment A1 to give (2S,4R)-1-(4-fluoro-benzoyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 484.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1[N:30]=[C:31]=[O:32])([CH3:20])[CH3:19].C([N-]C(C)C)(C)C.[Li+]>>[CH3:20][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:28])[CH3:29])[C:22]=1[NH:30][C:31](=[O:32])[CH2:10][C:9](=[O:11])[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:19]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(=O)CC(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)CC(c1ccccc1)c1ccccc1

Procedure:
The title compound, mp 146°-148° C., was prepared from 4,4-diphenylbutan-2-one (3.50 g, 0.015 mol), 2.6-diisopropylphenyl isocyanate (3.17 g, 0.015 mol) and lithium diisopropylamide (0.015 mol) using the procedure described in Example 1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH3:28])[C:7](=[O:27])[C:8]4[CH:18]=[C:17]([CH2:19][CH2:20][C:21]5[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=5)[CH:16]=[N:15][C:9]=4[N:10]([CH2:13][CH3:14])[C:11]=3[N:12]=2)=[CH:33][CH:32]=1
Reactant: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: COc1ccc(CN)cc1
Product: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(NCc3ccc(OC)cc3)nc21
Temperature: 150 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
A mixture of 2-chloro-5,11-dihydro-11-ethyl-8-[2-(4-pyridyl)ethyl]-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.285 g, 0.7 mmol) and 4-methoxybenzylamine (0.23 mL, 1.8 mmol) in 4 mL of xylenes was heated at 150° C. in a sealed tube. After 24 hours, additional amine (0.23 mL, 1.8 mmol) was added and the reaction temperature was increased to 250° C. Heat was removed after 2d, and the reaction mixture was washed with saturated aqueous ammonium chloride to remove excess amine. The organic layer was dried (magnesium sulfate) and concentrated. Purification by flash chromatography (elution with methanol-dichloromethane) afforded the title compound (0.09 g, 26%).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(O)C.C[O-].[Na+].[C:17]1([N:23]=[N:24][CH:25]([C:28]#[N:29])[C:26]#[N:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[C:17]1([N:23]=[N:24][C:25]2[C:26]([NH2:27])=[N:9][C:2]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:10][C:28]=2[NH2:29])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N=C(N)c1ccncc1
Reactant: N#CC(C#N)N=Nc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2ccncc2)nc(N)c1N=Nc1ccccc1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
The intermediate 5-(phenylazo)-2-(4-pyridinyl)-4,6-pyrimidinediamine was prepared as follows: a mixture containing 477 g of isonicotinamidine hydrochloride, 3 liters of ethanol and 170 g of sodium methoxide was stirred for 30 minutes and to the mixture was added 340 g of α-(phenylazo)malononitrile and the reaction mixture was stirred under reflux for 5 hours and then poured into 3 liters of water. The solid that separated was collected, washed with water and dried in a vacuum oven at 90°-95° C. to yield 356 g of 5-(phenylazo)-2-(4-pyridinyl)-4,6-pyrimidinediamine, m.p. 302°-305° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2)(=[O:19])[CH3:18]
Reactant: CCOC(=O)c1cc2cc(N)ccc2nn1
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2cc(NC(C)=O)ccc2nn1
Temperature: 100 °C

Procedure:
Ethyl 6-aminocinnolin-3-yl carboxylate (obtained as described below) was dissolved in acetic anhydride (25 ml.). The solution was heated at 100° C. for 16 hours and then allowed to cool to room temperature, and the resulting mixture was filtered to give, as solid residue, ethyl 6-acetylamino-cinnolin-3-yl carboxylate, m.p. 256°-258° C.
Reaction SMILES: C([N:8]1[CH2:12][C:11]([CH2:13][CH2:14][N:15]2[C@H:20]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:10][NH:9]1)C1C=CC=CC=1.CC([O-])(C)C.[K+]>CS(C)=O.C1COCC1>[CH3:34][C:33]1[C:28]([C@H:16]2[CH2:17][CH2:18][CH2:19][C@@H:20]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:15]2[CH2:14][CH2:13][C:11]2[CH:12]=[N:8][NH:9][CH:10]=2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCC1=CNN(Cc2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCc1cn[nH]c1
Temperature: 140 °C
Yield: 64.4 %

Procedure:
To a solution of (2′R,6′S)-1′-[2-(2-benzyl-1 H-pyrazol-4-yl)-ethyl]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.130 g, 0.288 mmol) in dry DMSO (0.70 mL) and THF (12 mL) was added 4 Å molecular sieve (˜1 g) pre-heated at 140° C., and KOtBu (0.600 g, 5.35 mmol). The solution was bubbled with air (pre-dried by passing through a NaOH column) at room temperature for 1 h. Saturated aqueous NH4Cl (20 mL) was then added. The mixture was filtered through a celite cake and the cake was washed with EtOAc throughout. The organic layer in the filtrate was collected, and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (200:10:1 CH2Cl2/CH3OH/NH4OH), affording a pale yellow solid (0.067 g, 64%) after precipitation from CH2Cl2/hexanes by evaporation under vacuum. 1HNMR(CDCl3) δ 1.60-1.85 (4H), 2.00-2.15 (m, 2H), 2.25-2.62 (m, 10H), 4.10-4.20 (m, 2H), 6.73 (s, 2H), 7.07-7.12 (m, 2H), 7.43 (d, 2H, J=7.2 Hz), 8.45 (s, br. 2H); 13C NMR (CD2Cl2) δ 19.02, 21.33, 25.61, 30.31, 50.86, 64.12, 118.85, 122.40, 132.22, 132.65, 138.78, 147.03, 160.46. ES-MS m/z 362 (M+H). Anal. Calcd. for C22H27N5.0.2H2O: C, 72.38; H, 7.56; N, 19.18. Found: C, 72.31; H, 7.70; N, 18.98.
Reaction SMILES: Cl[C:2](OCC)=O.[NH2:7][CH2:8][C:9]1([C:20]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:19]2[C:11](=[CH:12][C:13]3[S:17][CH:16]=[CH:15][C:14]=3[CH:18]=2)[CH2:10]1.C(N(CC)CC)C>ClCCl>[CH3:2][NH:7][CH2:8][C:9]1([C:20]2([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:19]2[C:11](=[CH:12][C:13]3[S:17][CH:16]=[CH:15][C:14]=3[CH:18]=2)[CH2:10]1
Reactant: CCOC(=O)Cl
Reactant: NCC1(C2(O)CCCC2)Cc2cc3sccc3cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNCC1(C2(O)CCCC2)Cc2cc3sccc3cc21

Procedure:
A solution of 0.29 ml of ethyl chloroformate in 40 ml of dichloromethane is introduced, at 0° C., to a mixture of 1 g of the product of Example 21, 1.2 ml of triethylamine and 60 ml of dichloromethane. After returning to room temperature, the reaction mixture is washed with 0.1N hydrochloric acid and then with a saturated sodium hydrogen carbonate solution, dried and then evaporated. The resulting residue is dissolved in 20 ml of tetrahydrofuran. The solution is added to a mixture of 1.3 g of AlLiH4 in 60 ml of tetrahydrofuran. The reaction mixture is refluxed for 3 hours and then hydrolysed with 0.65 ml of water, 0.45 ml of 20% sodium hydroxide solution and 2.1 ml of water. After filtration and concentration, the residue is purified by chromatography over silica gel (dichloromethane/ethanol/NH4OH: 95/5/0.5) and recrystallised from isopropyl ether to yield the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[CH:12]([S:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:18]([C:17]1[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=1[S:15][CH:12]([CH3:14])[CH3:13])=[O:19])[CH2:6][CH2:5]2
Reactant: Clc1ccc2c(c1)CCNC2
Reactant: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(Cl)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [33537-99-4]) and 2-isopropylsulfanyl-5-methanesulfonyl-benzoic acid (example 2.7). MS (m/e): 424.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28](I)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]([C:47]([F:50])([F:49])[F:48])[C:43]([NH2:46])=[N:44][CH:45]=2)O1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:40]5[CH:45]=[N:44][C:43]([NH2:46])=[C:42]([C:47]([F:50])([F:49])[F:48])[CH:41]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: COc1cc(-c2nn3c(I)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Yield: 7 %

Procedure:
A mixture of 4-[4-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxy-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (94 mg, 0.169 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (73 mg, 0.253 mmol, 1.5 eq), 1,4-dioxane (5 ml), K2CO3 (70 mg, 0.507 mmol, 3 eq), H2O (2 ml) and Pd(PPh3)2Cl2 (12 mg, 0.0169 mmol, 0.1 eq) was heated under microwave irradiation (120° C., 30 min). Solvents were removed and the residue was partitioned between H2O and EtOAc. The organic layer was dried, filtered and evaporated. The residue was purified in an Isolute Flash Si II column (10-25% EtOAc in c-hexane and 20% MeOH in DCM) and by HPLC-prep to give the desired product (7 mg) as a yellow solid. The aqueous phase was further extracted with MeOH/DCM 1:9, the organic layers were dried, filtered and evaporated. The residue was triturated with MeOH/DMSO, filtered and washed with CH3CN to give the desired product (18 mg, overall yield: 25%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=2.95 min, [M+H]+ m/z 591.2; 1H NMR (300 MHz, DMSO) δ 8.86 (d, J=1.8 Hz, 1H), 8.43 (d, J=2.1 Hz, 1H), 7.77 (s, 1H), 7.49 (m, 2H), 7.27 (d, J=9.2 Hz, 1H), 6.73 (s, 2H), 4.67 (m, 1H), 3.89 (s, 3H), 3.68 (m, 2H), 3.21 (m, 2H), 1.92 (m, 2H), 1.57 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](=[S:11])=[S:10]>CN(C=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[S:11][C:9]1=[S:10]
Reactant: Nc1cccnc1Cl
Reactant: S=C=S
Solvent: CN(C)C=O
Product: S=c1[nH]c2cccnc2s1
Yield: 90 %

Procedure:
A mixture of 6.43 g (50.0 mmols) of 3-amino-2-chloropyridine, 50 ml of carbon disulfide and 50 ml of DMF was heated under reflux for 6 days. An excess of carbon disulfide was evaporated under reduced pressure, and the residue was poured into 300 ml of ice water with stirring. The precipitated crystals was taken out by filtration and dried to afford 7.57 g (yield: 90%) of pyrido[3,2-d]thiazo-line-2-thione.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][CH2:9][C:10]([O-:12])=O.[C:16]([NH:19][CH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O.ClC(Cl)C>[C:16]([NH:19][CH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:10](=[O:12])[CH2:9][CH2:8][C:7]([O:14][CH3:15])=[O:13])[CH:27]=2)[CH2:22]1)(=[O:18])[CH3:17]
Reactant: COC(=O)CCC(=O)[O-]
Reactant: CC(=O)NCC1Cc2ccccc2C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1ccc2c(c1)CC(CNC(C)=O)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
46.4 g of oxalyl chloride and 2 drops of dimethyl-formamide were added to 48.3 g of monomethyl succinate dissolved in 840 ml of dichloroethane. The mixture was stirred at room temperature for 5 hours. Then, under ice cooling, 34.6 g of 2-(acetylaminomethyl)indane dissolved in 280 ml of dichloroethane and 97.6 g of anhydrous aluminum chloride were added to the reaction mixture. After the mixture was stirred for 1 hour, the reaction mixture was poured into ice water. After the organic layer was collected by separation, washed with water and dried, the solvent was removed to obtain 51.8 g of 2-(acetylaminomethyl)-5-(3-methoxycarbonylpropionyl)indane. m.p.: 139° to 140° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]2[N:24]([CH3:25])[C:15]3=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=[C:14]3[N:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C=O)C.[CH2:31]([S-:33])[CH3:32].[Na+]>O>[CH2:31]([S:33][C:2]1[C:3]([C:12]2[N:24]([CH3:25])[C:15]3=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=[C:14]3[N:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH3:32]
Reactant: Cn1c(-c2ncc(C(F)(F)F)cc2Cl)nc2cc(C(F)(F)F)cnc21
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cc(C(F)(F)F)cnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a mixture of 2-(3-chloro-5-trifluoromethylpyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.71 g) and DMF (4 ml) was added sodium ethanethiolate (0.24 g) while ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-(3-ethylsulfanyl-5-trifluoromethylpyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.76 g), which is hereinafter referred to as “the present compound 4”.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][C:20](=[O:22])[O:19][CH:18]([C:23]3[N:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[S:26][CH:27]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH-:32].[Na+].Cl>CO>[C:1]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([N:16]([CH2:21][C:20]([OH:19])=[O:22])[CH2:17][CH:18]([OH:32])[C:23]2[N:24]=[C:25]([C:28]([F:30])([F:29])[F:31])[S:26][CH:27]=2)[CH3:15])=[CH:11][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N2CC(=O)OC(c3csc(C(F)(F)F)n3)C2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)N(CC(=O)O)CC(O)c2csc(C(F)(F)F)n2)cc1
Temperature: 0 °C

Procedure:
1.4 g (0.0031 mol) of N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-6-one are dissolved in 10 ml of methanol. 3 ml (0.003 mol) of 1N sodium hydroxide solution are added to this stirred solution at room temperature. After 5 minutes 15 ml of ice-water are added, and the mixture is neutralised with 3 ml of 1N hydrochloric acid. The aqueous phase is extracted by shaking 3× with methylene chloride. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The resulting residue is purified on a silica gel column using methylene chloride methanol=20:1 as eluant. This results, after concentration, in colourless crystals.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[C:15]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:16]=[C:17]([CH3:24])[C:18]=1[S:19][CH2:20][N+:21]([O-:23])=[O:22].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:14]=[C:15]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:27])=[O:28])[CH:16]=[C:17]([CH3:24])[C:18]=1[S:19]([CH2:20][N+:21]([O-:23])=[O:22])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(NS(=O)(=O)c2ccccc2)cc(C)c1SC[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(NS(=O)(=O)c2ccccc2)cc(C)c1S(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.7 %

Procedure:
1.3 g (5.46 mmol) of 70-75% m-chloroperbenzoic acid are added rapidly to a solution of 2.2 g (6.24 mmol) of N-[3,5-dimethyl-4-[(nitromethyl)thio]phenyl]benzenesulphonamide in 79 ml of anhydrous chloroform. The reaction medium is stirred for 24 h at room temperature and then poured into a solution of 0.33 g (3.93 mmol) of sodium bicarbonate. The mixture is extracted with methylene chloride. The combined organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by successive chromatographies on a column of silica (eluent for the first chromatography: methylene chloride; eluent for the second chromatography; 2/1 hexane/ethyl acetate) and crystallization from hexane, to give 0.98 g (42%) of N-[3,5-dimethyl-4-[(nitromethyl)sulphinyl]phenyl]benzenesulphonamide.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:17]([O:19]CC)=[O:18])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc2ncn(Cc3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2ncn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.2 %

Procedure:
To a stirred solution of ethyl 3-benzyl-3H-benzo[d]imidazole-5-carboxylate (0.12 g, 0.43 mmol) in ethanol (10 mL) was added NaOH (0.12 g in 2 mL of H2O) and then the solution was stirred for 24 hr at room temperature. The reaction solution was then concentrated, diluted with water (10 mL) and then the pH was adjusted to ˜5 using 1N HCl. The aqueous layer was then saturated with NaCl and extracted with ethyl acetate (2×50 mL). Then organic layer was dried (MgSO4), filtered and then concentrated to provide 0.1 g (93%) of 3-benzyl-3H-benzo[d]imidazole-5-carboxylic acid as an off-white solid.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11]Br)=[CH:10][C:4]=2[O:3]1.[C-:14]#[N:15].[K+].[Br-].[K+]>O>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][C:14]#[N:15])=[CH:10][C:4]=2[O:3]1
Reactant: [C-]#N
Reactant: FC1(F)Oc2ccc(CBr)cc2O1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: N#CCc1ccc2c(c1)OC(F)(F)O2
Temperature: 0 °C
Yield: 65.8 %

Procedure:
To a solution of 2,2-difluoro-5-bromomethyl-1,3-benzodioxole (41.0 g) in absolute alcohol (160 ml) at 60°-70° C a hot solution of potassium cyanide (22.1 g, 0.34 mole) in water (30 ml) is added. There is a slight exotherm and within 5 minutes potassium bromide separates out of the reaction mixture. The reaction mixture is refluxed for 1.5 hours, cooled and added to ice-water. The mixture is extracted with ether (3×100 ml), the combined extracts are washed with water (2×50 ml), dried over sodium sulfate and evaporated to afford a dark oil. Vacuum distillation yields 21.2 g of product (64% yield); b.p. 64°-67° C (at 0.03 mm); i.r. (neat) 2255 cm-1 ; nmr (CCl4) δ 3.68 (S, 2H), 7.00 (S, 3H).