Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:3]=1[CH2:4][C:5]1[NH:9][CH:8]=[N:7][CH:6]=1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:28])=CC=1>C1COCC1.O>[Cl:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:2]([Cl:1])[C:3]=1[CH2:4][C:5]1[NH:9][C:8](=[S:28])[NH:7][CH:6]=1
Reactant: Clc1cccc(Cl)c1Cc1cnc[nH]1
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: S=c1[nH]cc(Cc2c(Cl)cccc2Cl)[nH]1
Reaction time: 3 h

Procedure:
A solution of 5-(2,6-dichloro-benzyl)-1H-imidazole (Intermediate A4) (0.34 g, 1.5 mmol) in THF (6 mL) and water (6 mL) was treated with NaHCO3 (1.2 g) at rt for 10 m. Phenyl chlorothionoformate (0.60 mL, ˜4.3 mmol) was added and stirring was continued for 3 h. The mixture was diluted with water (10 mL) and extracted with ether (4×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (6 mL) and treated with NEt3 (0.6 mL) for 18 h. The solvent was removed under vacuum and the product was washed on a glass frit with CH2Cl2 to give a white solid 4-(2,6-dichloro-benzyl)-1,3-dihydro-imidazole-2-thione (Compound 1) in ˜50% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[N:12]=2)=[CH:4][N:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.[Cl-].[Na+].O>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[N:3][CH:4]=3)[NH:9][CH:10]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Clc1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)c[nH]2)cn1
Reactant: C1CNCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1Cl
Temperature: 25 °C
Yield: 58.4 %

Procedure:
A solution of 2-Chloro-5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridine (72.8 g) and piperazine (61.8 g) in DMSO (478 mL) was heated to 105 degrees 16 hours. The reaction mixture was cooled to room temperature and diluted with 2500 mL half-saturated brine. The resultant precipitate was collected by filtration and triturated with 2000 mL hot methanol. The solids were collected by filtration, the mother liquor was concentrated to about 100 mL, and the additional precipitate was collected and combined with the original solids to provide 1-{5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (49 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:8]([CH:22]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)=[O:10])([O-:3])=[O:2].C=O.[C:32]([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:32][N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[O:10])[CH2:25][CH2:26]1
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCNCC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC(Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a mixture of 5-nitro-2-(4-piperidinylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide (80.0 mg) and 37% formaldehyde solution (192 mg) in methanol (4 mL) were added sodium cyanoborohydride (37.9 mg) and acetic acid (4 drops). After stirring for 2 hours at ambient temperature, the mixture was partitioned between an aqueous saturated sodium bicarbonate solution and chloroform. The organic layer was separated and washed with water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2-(1-methyl-4-piperidinylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (65.0 mg).
Reaction SMILES: [C:1](C=P(CCCC)(CCCC)CCCC)#N.[C:17]([C:19]1[CH:50]=[CH:49][C:22]([O:23][CH2:24][CH2:25][N:26]2[CH2:33][CH:32]3[O:34][CH:28]([CH2:29][N:30]([CH2:35][CH2:36][NH:37][S:38]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=4[F:48])(=[O:40])=[O:39])[CH2:31]3)[CH2:27]2)=[C:21]([F:51])[CH:20]=1)#[N:18].C1COCC1>CO>[C:17]([C:19]1[CH:50]=[CH:49][C:22]([O:23][CH2:24][CH2:25][N:26]2[CH2:33][CH:32]3[O:34][CH:28]([CH2:29][N:30]([CH2:35][CH2:36][N:37]([CH3:1])[S:38]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:42]=4[F:48])(=[O:40])=[O:39])[CH2:31]3)[CH2:27]2)=[C:21]([F:51])[CH:20]=1)#[N:18]
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Reactant: N#Cc1ccc(OCCN2CC3CN(CCNS(=O)(=O)c4ccc(F)cc4F)CC(C2)O3)c(F)c1
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCN1CC2CN(CCOc3ccc(C#N)cc3F)CC(C1)O2)S(=O)(=O)c1ccc(F)cc1F
Temperature: 160 °C
Yield: 52.4 %

Procedure:
Cyanomethylenetri-n-butylphosphorane (90%, 0.158 g, 0.59 mmol) was weighed into a microwave vial. N-(2-{7-[2-(4-Cyano-2-fluoro-phenoxy)-ethyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl}-ethyl)-2,4-difluoro-benzenesulfonamide (100 mg, 0.2 mmol, from example 11 above) and THF (2 mL) were added. Methanol (16 μl, 0.39 mmol) was then added and the reaction was heated with microwave irradiation at 160° C. for 15 min. MeOH (1 mL) was added and the reaction was heated with microwave irradiation for a further 10 min in order to consume excess reagent. The reaction mixture was concentrated and the crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent. The product isolated could be purified further by recrystallisation from MeOH to give a solid (55 mg, 53%).
Reaction SMILES: [BH4-].[Na+].O=[C:4]1[C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:6](=[O:20])[O:5]1.Cl.C(O)C>C1COCC1.[Cl-].[Na+].O>[O:20]=[C:6]1[O:5][CH2:4][C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1
Reactant: O=C1C[C@@H](NC(=O)OCc2ccccc2)C(=O)O1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C1C[C@@H](NC(=O)OCc2ccccc2)CO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
A suspension of NaBH4 (2.71 g, 71.5 mmol) in THF (50 mL) was cooled to 0° C., treated dropwise with a solution of EXAMPLE 21A (16.21 g, 65.0 mmol) in THF (50 mL), allowed to warm to room temperature, and stirred for 2 hours. The resulting mixture was treated with concentrated HCl (13.1 mL) and ethanol (13.1 mL), heated to reflux for 12 hours, allowed to cool to room temperature, poured into brine (100 mL) and the layers were separated. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was triturated with diethyl ether (50 mL) for 2 hours, cooled overnight, and the solid collected by filtration to provide the desired product (7.81 g, 51%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17]([N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1)[CH3:18]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([N:19]1[C:23]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[CH:22][CH:21]=[N:20]1)[CH3:18]
Reactant: CCn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1nccc1-c1csc(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a solution of methyl 4-bromo-2-thiophenecarboxylate (1.0 g, 4.52 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (1.86 g, 13.5 mmol), tetrakistriphenylphosphine Pd(0) (260 mg, 0.23 mmol) and 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.3 g, 5.85 mmol). The reaction mixture was heated to 70° C. in a sealed tube. After 2 h, the reaction mixture was concentrated under vacuum and purified on silica (hex/EtOAc, 20-40%) to afford methyl 4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.7 g, 66%) as a light yellow solid: LC-MS (ES) m/z=237 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[CH2:11]=[C:12]1[C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:15][C:14](=[O:22])[N:13]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:11]=[C:12]1[C:16]2([CH2:21][CH2:20][N:19]([C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:9])[CH2:18][CH2:17]2)[O:15][C:14](=[O:22])[N:13]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=C1N(c2ccccc2)C(=O)OC12CCNCC2
Reactant: CN1CCN(C(=O)Cl)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C1N(c2ccccc2)C(=O)OC12CCN(C(=O)N1CCN(C)CC1)CC2
Yield: 83 %

Procedure:
The solution of 3.9 g of 4-methylpiperazin-1-yl-carbonyl chloride in 5 ml of chloroform is dropwise added at a temperature between 0° and 5° C. to a solution containing 4.9 g of 4-methylene-2-oxo-3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane and 7.4 ml of triethylamine in 74 ml of chloroform under stirring. Thereafter, the reaction mixture is stirred at room temperature for an additional 30 minutes. After termination of the reaction the chloroform phase is washed to chloride-free with water, dried over anhydrous sodium sulfate, then the solvent is evaporated under reduced pressure. After recrystallization of the crude product obtained from ethanol under clarifying by activated carbon the title compound is obtained in 83% yield, m.p.: 198°-199° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Reactant: ClCCN1CCCC1
Product: CC(C)(C)OC(=O)N1CCC(=O)N(CCN2CCCC2)CC1

Procedure:
In analogy to the procedure described in intermediate 4A, 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester and 1-(2-chloro-ethyl)-pyrrolidine gave the title compound as light yellow solid. MS: 312.0 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1[OH:26].O>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:14]=1[O:26][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: BrCCCBr
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.7 %

Procedure:
A reaction vessel was charged with 10.6 g of 1,3-dibromopropane, 5.53 g of potassium carbonate and 100 ml of N,N-dimethylformamide, to which a solution of 30.5 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol dissolved in 40 ml of N,N-dimethylformamide was slowly added dropwise. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with 150 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 11.1 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (77% yield), nD24.0 1.5693.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[C:38](Cl)=[N:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:27][C@H:21]2[C:20](=[O:40])[NH:19][C@:18]2([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:41][C@@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)C1S[C:54]2[CH:60]=[CH:59][CH:58]=[CH:57][C:55]=2N=1)CCC.O1CCOCC1>CC#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[C:38]([C:54]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:55]=4)=[N:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:27][C@H:21]2[C:20](=[O:40])[NH:19][C@:18]2([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:41][C@@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Reactant: CCOC(=O)[C@@]12C[C@@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4nc3Cl)C[C@H]1C(=O)N2
Agent: [Pd]
Agent: CCOC(=O)[C@@]12C[C@@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4nc3-c3ccccc3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4nc3Cl)C[C@H]1C(=O)N2
Solvent: C1COCCO1
Solvent: CC#N
Product: CCOC(=O)[C@@]12C[C@@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4nc3-c3ccccc3)C[C@H]1C(=O)N2
Reaction time: 1 h

Procedure:
To a microwave vessel was added the product from 1b (700 mg. 1.07 mmole), 2-(tributylstannyl)benzo[d]thiazole (905 mg, 2.13 mmole), palladium-tetrakis(triphenylphosphine) (113 mg, 0.11 mmole) and dioxane (5 ml). The vessel was evacuated and nitrogen introduced, which was repeated twice. The mixture was reacted in a microwave reactor at 110 degrees C. for 1 hr. The reaction was diluted with MeCN and washed 3 times with hexane. The MeCN layer was evaporated and purified by column chromatography on silica gel (CHCl3-EtOAc gradient) to obtain the title compound (692 mg, 86% yield). MS(ESI): m/z=755.2 [M+H].
Reaction SMILES: [Cl-].CS(C)=O.[CH3:6][O:7][C:8](=[O:23])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([CH2:19][CH2:20][CH2:21][OH:22])[CH:10]=1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[CH3:6][O:7][C:8](=[O:23])[C:9]1[CH:10]=[C:11]([CH2:19][CH2:20][CH:21]=[O:22])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=1
Reactant: COC(=O)c1cc(CCCO)c(OC)c(OC)c1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(CCC=O)c(OC)c(OC)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 92.9 %

Procedure:
To a solution of oxallyl chloride (1.34 mL, 15.4 mmol) in CH2Cl2 (30 mL) at −78° C. was added a solution of dimethyl sulfoxide (DMSO) (1.45 mL, 20.5 mmol) in CH2Cl2 (10 mL) via cannula over the course of 1 min. After stirring for 20 min at −78° C. a solution of 3-(3-hydroxypropyl)-4,5-dimethoxybenzoic acid methyl ester (1.30 g, 5.12 mmol) in CH2Cl2 (10 mL) was added via syringe. The reaction was stirred at −78° C. for 45 min then treated with triethylamine (Et3N) (5.7 mL, 10 eq.). After 20 min at −78° C. the reaction was allowed to warm to room temperature. After stirring at room temperature for 30 min, the reaction mixture was diluted with 1:1 EtOAc:hexanes (250 mL), washed with H2O (2×200 mL), brine (200 mL), dried over MgSO4 and then concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 50% EtOAc in hexanes as an eluent to furnish 3,4-dimethoxy-5-(3-oxopropyl)benzoic acid methyl ester (1.20 g, 93%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]=[S:26]1(=[O:40])[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:22])[NH:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][N:29]4[CH2:28][CH2:27][S:26](=[O:25])(=[O:40])[CH2:31][CH2:30]4)=[CH:34][CH:35]=3)=[CH:19][CH:20]=2)[C:12]([CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1-c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 118 h
Yield: 82.6 %

Procedure:
A mixture of 5′-tert-butoxycarbonylamino-2′-methyl-biphenyl-4-carboxylic acid (500 mg), 4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl) -phenylamine (367 mg), triethylamine (0.64 ml) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (869 mg) in dry DMF (20 ml) was stirred at 20 C for 118 h. The mixture was then partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with ethyl acetate:petrol; 1:1 removed high Rf impurities and further elution with ethyl acetate gave the title compound as a pale yellow solid (693 mg).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][CH2:10][C:11]([C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)=O)=[O:8])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([C:7]2[O:8][C:11]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=3)=[CH:10][N:9]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1ccc(C(=O)CNC(=O)c2ccc(C(F)(F)F)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2cnc(-c3ccc(C(F)(F)F)cc3)o2)cc1
Yield: 60 %

Procedure:
In the same manner as in Example 106, ethyl 4-[2-(4-trifluoromethylbenzoylamino)-1-oxoethyl]benzoate was reacted with phosphorus oxychloride to obtain ethyl 4-[2-(4-trifluoromethylphenyl)-5-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 60%. Pale yellow prisms. Melting point: 142 to 143° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][OH:10]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[O:10]
Reactant: Nc1cccc(F)c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Nc1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.44 g (10.2 mmol) (2-amino-6-fluoro-phenyl)-methanol are dissolved in 120 ml chloroform, combined with 4.43 g (51 mmol) manganese(IV)-oxide and stirred for 2 days at ambient temperature. Then excess manganese(IV)-oxide is filtered off through Celite and the solvent is eliminated in vacuo.
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:5][CH2:4][CH2:3]1.S(=O)(=O)(O)O.[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH3:22])[CH:21]=1)[NH:18][N:17]=[CH:16]2.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:12][C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:15](=[CH:16][N:17]([C:2]3([CH3:1])[CH2:5][CH2:4][CH2:3]3)[N:18]=2)[CH:14]=1
Reactant: CC1(O)CCC1
Reactant: Cc1cc(Br)cc2cn[nH]c12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc2cn(C3(C)CCC3)nc12

Procedure:
1-Methyl-1-cyclobutanol (3 mL) and concentrated sulfuric acid (0.1 mL) were added to 5-bromo-7-methyl-1H-indazole (633 mg). The reaction solution was allowed to react in a microwave reactor at 100° C. for 30 minutes, and then further allowed to react at 120° C. for 30 minutes. An aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution. After separation, the organic layer was washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum, and the resultant was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 5-bromo-7-methyl-2-(1-methylcyclobutyl)-2H-indazole.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](Br)[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24]>CC(C)=O>[C:25]1([C:23](=[O:24])[CH2:22][N:12]2[CH2:13][CH2:14][CH:15]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=3)[CH2:11]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COc1cccc(C2=CCCNC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cccc(C2=CCCN(CC(=O)c3ccccc3)C2)c1
Yield: 102.8 %

Procedure:
A mixture of 10 g of 3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine hydrochloride, 200 ml of acetone, 14 g of sodium carbonate and 9.3 g of phenacyl bromide were refluxed for 3 hours and was filtered. The filtrate was evaporated to dryness to obtain 14 g of 1-phenyl-2-[3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridin-1-yl]-ethanone.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]4[CH2:23][N:22]([C:24](OC(C)(C)C)=O)[CH2:21][CH2:20][O:19][C:15]4=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)([C:33](F)(F)[F:34])=O.C(N(CC)CC)C.FCCI>C(Cl)Cl>[F:34][CH2:33][CH2:24][N:22]1[CH2:23][C:14]2=[C:13]3[C:18](=[CH:17][CH:16]=[C:15]2[O:19][CH2:20][CH2:21]1)[N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[CH:11]=[CH:12]3
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Agent: FCCI
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2c3c(ccc21)OCCN(CCF)C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 17, 16 mg, 0.040 mmol) was dissolved in DCM (1 mL) and TFA (0.5 mL) was added. The reaction mixture was heated to reflux, and immediately allowed to cool to room temperature. The solution was evaporated and the residue was dissolved in DMF (0.5 mL). Triethylamine (0.011 mL, 0.080 mmol) was added and the reaction mixture was stirred for 5 minutes before 1-fluoro-2-iodoethane (0.063 mL, 0.080 mmol) was added. The solution was stirred at 60° C. overnight. The solution was evaporated and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (6.9 mg). MS m/z 375 [M+H]+.
Reaction SMILES: O=[C:2]([CH3:26])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH2:15][CH:14]3[CH2:18][S:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:13]3=[N:12]2)=[CH:7][CH:6]=1.Cl.[CH3:28][NH:29][CH3:30].C(B)#N.[Na]>C(O)C>[CH3:28][N:29]([CH3:30])[CH:2]([CH3:26])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH2:15][CH:14]3[CH2:18][S:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:13]3=[N:12]2)=[CH:7][CH:6]=1
Reactant: CC(=O)COc1ccc(N2N=C3c4ccccc4SCC3CC2=O)cc1
Reactant: CNC
Agent: BC#N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(COc1ccc(N2N=C3c4ccccc4SCC3CC2=O)cc1)N(C)C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a mixture of 3.6 g of 2-[4-(2-oxopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one, 3.3 g of dimethylamine hydrochloride and 50 ml of ethanol is added dropwise 20 ml of a solution of 1 g of sodium cyanoboron hydride in 20 ml of ethanol while stirring under heating and reflux over 1 hour. The mixture is stirred under heating and reflux for further 4 hours. After the completion of the reaction, the solvent is distilled off, and water and dilute hydrochloric acid are added to the residue. After the mixture is left standing still for 30 minutes, it is neutralized with potassium carbonate and extracted with chloroform. The extract is dried over magnesium sulfate, and the solvent is distilled off. The residue is purified by silica gel column chromatography (chloroform:methanol =10:1 ) and then converted into the fumarate in acetone, which is recrystallized from ethanol to give 3.4 g of 2-[4-(2-dimethylaminopropoxy)phenyl]-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one.fumarate as white crystals, m.p. 171°-173° C.