Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14]3)[C:6]=2[N:19]=1.IC.[CH3:22]N(C)C(=O)C.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14]3)[C:6]=2[N:19]=1
Reactant: CC1CCC(N2CCC(=O)Nc3cnc(Cl)nc32)C1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC1CCC(N2CCC(=O)N(C)c3cnc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.14 g (0.0005 mole) of (rac)-2-chloro-9-(3-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-58), 0.047 mL (0.00075 mole) of iodomethane and 1 mL of N,N-dimethylacetamide at 0 degrees, was added 0.03 g (0.00075 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.132 g of (rac)-2-chloro-5-methyl-9-(3-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-58) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1.C(OC([N:35]1[CH:39]=[C:38]([NH2:40])[CH:37]=[N:36]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:35]1[CH:39]=[C:38]([NH:40][C:23]([C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][C:11]4[N:17]([N:18]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:1])([F:27])[F:26])[N:5]=[CH:6][N:7]=5)[CH:10]=4)[C:16]=3[CH:19]=2)=[O:25])[CH:37]=[N:36]1
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Reactant: O=C(O)c1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cn[nH]c1)c1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Following the procedure for 126, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 4-amino-pyrazole-1-carboxylic acid tert-butyl ester. The intermediate carboxylic acid tert-butyl ester was dissolved in DCM (5 mL) and treated with TFA (2 mL) before the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue triturated in water to give 127 as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.53 (s, 1H); 8.51 (d, J=2.2 Hz, 1H); 8.23 (s, 1H); 7.96 (dd, J=8.5, 2.2 Hz, 1H); 7.84 (s, 2H); 7.39 (d, J=8.5 Hz, 1H); 7.02 (s, 1H); 5.77 (q, J=8.7 Hz, 2H); 4.59 (t, J=5.8 Hz, 2H). 3 Protons obscured by water peak. LCMS: RT=9.11 min, M+H+=445
Reaction SMILES: [OH-].[K+].O.NN.[CH3:6][O:7][C:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][C:9]2=O>C(O)CO>[CH3:6][O:7][C:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][CH2:9]2
Reactant: COC12CCC(CC1)CC2=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COC12CCC(CC1)CC2
Temperature: 195 °C
Yield: 44.9 %

Procedure:
To a solution of potassium hydroxide (17 g, 250 mmol) and 85% hydrazine hydrate (11.5 g, 186 mmol) in ethylene glycol (220 mL) was added 1-methoxybicyclo[2.2.2]octan-2-one (11.0 g, 71.4 mmol). The mixture was heated to 195° C. over 1 h and heated for an additional hour. The flask was then fitted for distillation, and approximate 20 mL (two layers) of liquid was collected over a period of 1 h at 195° C. Subsequent dropwise addition of water (215 mL) to the reaction over a period of 3 h afforded a second fraction of distillates (approximately 180 mL). The combined distillates were extracted with ether (3×80 mL), the organic phase was dried over Na2SO4, and the volatiles were removed to produce 1-methoxybicyclo[2.2.2]octane (4.5 g, 45%) which was used in the next step directly without purification. 1H NMR (CDCl3, 400 MHz) δ 3.14 (s, 3H), 1.63-1.59 (m, 6H), 1.58-1.51 (m, 6H), 1.47 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=O)[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[O:27][CH3:28]>>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][NH:17][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[F:16])=[C:20]([O:27][CH3:28])[CH:21]=1)#[N:24]
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Reactant: COc1cc(C#N)ccc1CN
Product: CCOC(C(=O)NCc1ccc(C#N)cc1OC)c1ccc(OC)cc1F

Procedure:
(RS)-Ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid, described in example 63.1 was coupled with 4-aminomethyl-3-methoxy-benzonitrile (CAS 182159-14-4) according to general procedure B to give (RS)-N-(4-cyano-2-methoxy-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Yellow oil. MS 373.2 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[Cl:6].C(N(CC)CC)C.[CH2:22]([N:24]([CH2:28][CH3:29])[C:25](Cl)=[O:26])[CH3:23]>C1C=CC=CC=1>[Cl:6][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:4]([O:14][C:25](=[O:26])[N:24]([CH2:28][CH3:29])[CH2:22][CH3:23])=[N:3][O:2][CH3:1]
Reactant: CCN(CC)C(=O)Cl
Reactant: CONC(=O)C(Cl)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)OC(=NOC)C(Cl)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
N-Methoxy-α-(4-chlorophenyl)-α-chloroacetamide (23.3 grams; 0.1 mole), benzene (100 ml), and triethylamine (12 grams; 0.12 mole) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. N,N-Diethylcarbamoyl chloride (13.5 grams; 0.1 mole) dissolved in benzene (25 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-1-(4-chlorophenyl)-2-(N,N-diethylcarbamoyloxy)-2-methoxyiminoethane.
Reaction SMILES: S(Cl)(Cl)=O.Cl.[Cl:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:16]O>>[Cl:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CO
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccnc1Cl

Procedure:
Thionyl chloride (3.8 g.) was added dropwise, over 10 minutes, to a solution of 2-chloropyridin-3-carboxylic acid HCl salt (1.0 g.) in methanol, stirred under an inert atmosphere and cooled in an ice/salt bath. The reaction was stirred for a further 5 days at ambient temperature. The methanol was evaporated away and the residue treated with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were dried and evaporated to dryness to give methyl 2-chloropyridin-3-carboxylate as a colourless liquid (0.9 g.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH:7]=1.[CH3:41][C:42]([C:45]([NH2:47])=[O:46])([CH3:44])[NH2:43]>>[NH2:47][C:45](=[O:46])[C:42]([NH:43][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([N:17]2[C:18]3[C:14](=[C:13]([NH:12][CH2:11][C:10]([OH:36])([C:32]([F:33])([F:34])[F:35])[CH2:9][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:39][CH3:40])([CH3:38])[CH3:37])[CH:21]=[C:20]([CH3:22])[CH:19]=3)[CH:15]=[N:16]2)[CH:24]=1)([CH3:44])[CH3:41]
Reactant: CC(C)(N)C(N)=O
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)NC(C)(C)C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and 2-methylalaninamide.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].[CH3:17][Li]>CCOCC>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:17])=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2]
Reactant: [Li]C
Reactant: CCc1sc(C(=O)O)c2c1CC(C)(C)CC2
Solvent: CCOCC
Product: CCc1sc(C(C)=O)c2c1CC(C)(C)CC2
Reaction time: 0.25 h

Procedure:
To a solution of 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.10 g, 8.81 mmol) in Et2O (100 mL), a solution of methyllithium (11 mL, 1.6 M solution in Et2O) is added at rt. The pale yellow solution is stirred at rt for 15 min before another portion of methyllithium (2 mL) is added. Stirring is continued for 15 min, a further portion of methyllithium (1 mL) is added, and the mixture is again stirred for 15 min at rt. The reaction is quenched with water. The organic layer is separated, washed once more with water, dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (1.65 g) as a pale yellow solid; LC-MS: tR=1.00 min, [M+1]=237.15; 1H NMR (CDCl3): δ 3.03 (t, J=7.0 Hz, 2H), 2.73 (q, J=7.6 Hz, 2H), 2.47 (s, 3H), 2.31 (s, 2H), 1.55 (t, J=7.0 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H), 0.97 (s, 6H).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Cl.O>CS(C)=O>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][N:5]1[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]1
Reactant: ClCc1ccccc1Cl
Reactant: Cc1cc(C)[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)n(Cc2ccccc2Cl)n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
Powdered potassium hydroxide (1.751 g, 31.2 mmol) was added to a solution of 3,5-dimethylpyrazole (2 g, 20.81 mmol) in anhydrous DMSO (10.40 ml) and the resulting heterogeneous solution was stirred for 1.5 hr at 80° C. before being cooled to room temperature. 2-Chloro benzylchloride (2.64 ml, 20.81 mmol) was then added in 6 M DMSO over 15 min, and the solution was stirred for a further 1.5 hrs. Upon completion as observed by TLC, the reaction was poured over water and the resulting aqueous phase was extracted with two 20 mL portions of CHCl3. The combined organic layers were washed with 100 mL of water, dried with anhydrous MgSO4 and concentrated under reduced pressure to yield 4.55 g (99%) of 1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazole as a clear liquid. 1H NMR (300 MHz, CDCl3) δ 7.41-7.31 (m, 1H), 7.24-7.09 (m, 2H), 6.59-6.50 (m, 1H), 5.90 (s, 1H), 5.31 (s, 2H), 2.26 (s, 3H), 2.15 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 148.32, 139.96, 135.46, 131.96, 129.42, 128.76, 127.72, 127.48, 105.84, 50.12, 13.80, 11.15. HRMS (m/z): [MNa]+ calc for C12H13ClN2Na+243.07. found 243.0651.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([Si:20]([O:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].CN([CH:36]=[O:37])C>C1COCC1>[Si:20]([O:23][CH2:24][CH2:25][C:26]1[C:27]([F:32])=[C:28]([CH:29]=[CH:30][CH:31]=1)[CH:36]=[O:37])([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:21])[CH3:22]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1F
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(C=O)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,2,6,6-tetramethylpiperidine (11.0 g) in anhydrous THF (200 mL) was cooled to −78° and treated with butyllithium (37.5 mL), added steadily over 5 minutes via a syringe. The solution was stirred at −78° for 15 minutes and then treated with a solution of tert-butyl(2-fluorophenethoxy)dimethylsilane [Aromatic Intermediate 5, step a] (9.9 g) in THF (25 mL), added dropwise over 15 minutes. The solution that was stirred at −78° for 2 hours, then treated with a solution of DMF (9.0 mL) in THF (25 mL), added dropwise over 10 minutes. The solution was stirred at −78° for 1 hour, then the cooling bath was removed and the solution was allowed to warm to room temperature overnight. The reaction mixture was poured into aqueous HCl (0.5 M) and extracted three times with ethyl acetate. The combined organic phases were washed three times with water, once with brine, then dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the titled compound. Yield 10.1 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2[CH3:20])[CH2:4][O:3]1.[CH2:22](C1C=C(C=C(C)C=1O)C#N)C>>[CH3:1][C:2]1([CH3:21])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:17][C:18]=2[CH2:19][CH3:22])[CH2:4][O:3]1
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Product: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1

Procedure:
The title compound is obtained as a beige oil (0.86 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 3-ethyl-4-hydroxy-5-methyl-benzonitrile and L-alpha-beta-isopropyliden glycerol; LC-MS: tR=0.67 min, [M+H]+=308.99.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13](C(OC(C)(C)C)=O)[N:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O.ClCCl>[C:1]1([NH:7][C:8]([NH:10][C:11]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][NH:13][N:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)nc1NC(=O)Nc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c[nH]nc1NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 3-amino-4-ethoxycarbonylpyrazole (1.0 g) in THF (10 ml), was added di-tert-butyl dicarbonate (2.2 g), and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated under reduced pressure followed by silica-gel column chromatography (toluene/ethyl acetate=15/1) to give 3-amino-1(tert-butoxycarbonyl)-4-ethoxycarbonylpyrazole (0.59 g). This intermediate was derived to N-phenyl-N'-(1-tert-butoxycarbonyl-4-ethoxycarbonylpyrazol-3-yl)urea by the similar method to Reference Example 1 (yield 75%). N-phenyl-N'-(1-tertbutoxycarbonyl-4-ethoxycarbonylpyrazol-3-yl)urea (0.5 g) was dissolved in a solution of 10% trifluoroacetic acid in dichloromethane (7 ml), and the resulted solution was stirred overnight at room temperature. The reaction mixture was evaporated under reduced pressure followed by addition of ether to give the title compound (0.304 g, yield 83%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccn1)C1CCNCC1
Yield: 99.3 %

Procedure:
To a solution of compound 4-(pyridine-2-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (260 mg, 0.90 mmol) in dichloromethane (10 mL) was then added TFA (0.69 mL, 8.95 mmol) the reaction was then stirred at 25° C. for 3 hours and the solvent was removed under vacuum and the crude material was co-evaporated 3 times with dichloromethane to remove most of the remaining TFA, affording crude the title compound as an orange oil (170 mg, 100%). The crude material was used directly in the next step without subsequent purification. LRMS m/z ES+=190.8 (M+H), retention time 0.60.
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][CH:11]1[C:15]23[CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=[CH:21][CH:20]=[C:16]2[N:17]=[CH:18][CH:19]=[C:14]3[S:13][CH2:12]1.Cl>C(O)(C)C.CO>[CH3:10][CH:11]1[C:15]23[CH:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:22]=[CH:21][CH:20]=[C:16]2[N:17]=[CH:18][CH:19]=[C:14]3[S:13][CH:12]1[CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1CSC2=CC=NC3=CC=CC(c4ccccc4)C321
Reactant: BrCCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CC1C(CCc2ccccc2)SC2=CC=NC3=CC=CC(c4ccccc4)C321

Procedure:
Phenethyl bromide is condensed with 3-methyl-4-phenyl-1,2,3,4-tetrahydro-benzo(b)thieno[3,2-c]pyridine (Example 2) according to the procedure described in Example 6. Hydrochloride: white crytals, m.p. 210° C. (isopropanol-methanol); Yield : 72%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:15]([CH2:16][CH2:17][CH3:18])[N:14]=[C:13]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[C:12]=2[C:26]([F:29])([F:28])[F:27])=[O:10])=[CH:4][C:3]=1[C:30](=[O:37])[NH:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:45][CH3:46]>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:45][CH3:46])[C:9]([C:11]2[N:15]([CH2:16][CH2:17][CH3:18])[N:14]=[C:13]([C:19]([F:25])([F:24])[C:20]([F:23])([F:21])[F:22])[C:12]=2[C:26]([F:29])([F:27])[F:28])=[O:10])=[CH:4][C:3]=1[C:30](=[O:37])[NH:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1
Reactant: CCCn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C(=O)NC2(C#N)CC2)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)N(CC)c1ccc(Cl)c(C(=O)NC2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
70 mg (0.13 mmol) of N-{4-chloro-3-[(1-cyanocyclopropyl)carbamoyl]phenyl}-3-(pentafluoroethyl)-1-propyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide and 35 mg (0.14 mmol) of potassium carbonate are suspended in 1.4 ml of N,N-dimethylformamide p.a. Over a period of 16 h, a total of 29 mg (0.19 mmol) of iodoethane are added gradually to the mixture. After the addition has ended, the reaction solution is stirred at room temperature for 20 h. The reaction mixture is diluted with water, and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulphate and filtered. The solvents are removed on a rotary evaporator under reduced pressure.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[S:17](N)(N)(=[O:19])=[O:18]>COCCOCCOC>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]1[C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[CH2:2][NH:1][S:17]1(=[O:19])=[O:18]
Reactant: NCc1ccccc1Nc1ccccc1F
Reactant: NS(N)(=O)=O
Solvent: COCCOCCOC
Product: O=S1(=O)NCc2ccccc2N1c1ccccc1F
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of 2-(aminomethyl)-N-(2-fluorophenyl)aniline (2.07 g, 9.6 mmol) and sulfamide (1.1 g, 11.5 mmol) in digylyme (10 mL) was added to a flask containing refluxing diglyme (15 mL) over 10 min. The reaction mixture was stirred at reflux for 1 h, then cooled to room temperature and was evaporated to a brown oil. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/heptane) to afford 1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (1.86 g, 70%) as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].CC1C=CC(S(O[CH2:33][C@H:34]2[CH2:38][CH2:37][CH2:36][O:35]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:33][C@H:34]1[CH2:38][CH2:37][CH2:36][O:35]1)[C:11]3=[O:19]
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: BrCC1CCCCO1
Product: COc1cc2c(cc1C)C1(CO2)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 6-methoxy-5-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (72%) as a colorless solid: mp 151-153° C.; 1H NMR (300 MHz, CDCl3) δ7.27 (dd, J=7.7, 7.7 Hz, 1H), 7.15-6.98 (m, 3H), 6.48 (s, 1H), 6.44 (s, 1H), 4.90 (d, J=8.9 Hz, 1H), 4.65 (dd, J=8.9, 2.3 Hz, 1H), 4.32-4.21 (m, 1H), 3.99-3.61 (m, 4H), 3.78 (s, 3H), 2.10-1.63 (m, 4H), 1.99 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.3 (2), 160.3, 159.1, 142.9 (2), 132.6 (2), 128.7 (2), 124.2 (2), 123.7 (2), 119.5 (2), 119.2 (2), 109.5 (2), 93.7, 80.4 (2), 77.0 (2), 68.2 (2), 57.9, 55.5, 44.6 (2), 29.1 (2), 25.6 (2), 15.9 (2); MS (ES+) m/z 366.3 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[O:11])[S:7][CH:8]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].CCN(CC)CC>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[CH2:28][NH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:21])=[O:11])[S:7][CH:8]=1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCN)cs2)c(C(=O)C2CCCC2)c1
Reactant: COC(=O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNCCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To 1-[4-(amino-ethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (0.03 g, 0.08 mmol) in 10 mL DCM was added methyl bromoacetate (0.01 g, 0.08 mmol) followed by Et3N (0.008 g, 0.08 mmol). After stirring at room temperature overnight, reaction was concentrated and purified by flash chromatography on silica gel with 5% MeOH/EtOAc to obtain the product in 50% yield.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[C:27]([Cl:28])[C:22]=4[C:21](=[O:30])[N:20]4[CH2:31][CH2:32][C@H:19]4[C:18]=23)[N:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[Cl:28][C:27]1[C:22]2[C:21](=[O:30])[N:20]3[CH2:31][CH2:32][C@H:19]3[C:18]3[N:17]([CH:16]=[N:15][C:14]=3[C:11]3[N:10]=[C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[O:13][N:12]=3)[C:23]=2[CH:24]=[CH:25][C:26]=1[F:29]
Reactant: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)no1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3ccc(F)c2Cl)no1
Yield: 79.8 %

Procedure:
2.27 g (5 mmol) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were hydrogenated in 80 ml of ethyl acetate in the presence of 35 mg of 5% palladium-on-charcoal at room temperature and normal pressure. After separating the catalyst the reaction mixture was purified by chromatography on silica gel while eluting with ethyl acetate. There were obtained 1.83 g (80%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride.