Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[OH:14][CH2:15][C@@H:16]1[O:20][C:19]([C:21]2[NH:25][C:24]([C:26]3[CH:27]=[C:28]([OH:38])[CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:31]=3)=[CH:23][CH:22]=2)=[N:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:11]1([S:8]([C:5]2[N:6]=[CH:7][C:2]([O:38][C:28]3[CH:27]=[C:26]([C:24]4[NH:25][C:21]([C:19]5[O:20][C@@H:16]([CH2:15][OH:14])[CH2:17][N:18]=5)=[CH:22][CH:23]=4)[CH:31]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35][CH3:36])[CH:29]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:13][CH2:12]1
Reactant: O=S(=O)(c1ccc(Cl)cn1)C1CC1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)C3CC3)nc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
5-Chloro-2-(cyclopropylsulfonyl)pyridine (168 mg, 0.77 mmol) synthesized in Example (125c) and 3-{5-[(5R)-5-(Hydroxylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (401 mg, 1.16 mmol) synthesized in Example (125g) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (213 mg, 154 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (30 mL) was added, and extraction was carried out twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0.5%-5%) to afford the desired compound (139 mg, yield 34%) as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:22][O:23][CH2:24][CH3:25])[N:18]([CH2:19][CH2:20]O)[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.CO.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[ClH:3].[Cl:3][CH2:20][CH2:19][N:18]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:5])[C:15]=2[N:16]=[C:17]1[CH2:22][O:23][CH2:24][CH3:25]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCl
Product: Cl
Temperature: 25 °C

Procedure:
Thionyl chloride (5 mL) and 4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol (1 g) were combined and heated on a steam bath until thin layer chromatography (20% methanol/ethyl acetate) showed the disappearance of starting material. The reaction mixture was cooled to ambient temperature and then slowly poured into a mixture of ice and water. The mixture was neutralized with sodium bicarbonate and then extracted 3 times with dichloromethane. The extracts were combined, washed 3 times with aqueous sodium bicarbonate, dried with magnesium sulfate, filtered and then concentrated under vacuum. Acetone (about 10 mL) was added to the residue followed by methanolic hydrogen chloride (about 1 mL). The mixture was refluxed and a precipitate formed. The reaction mixture was cooled to ambient temperature. The precipitate was isolated by filtration and then washed with acetone. The solid was dissolved in hot methanol and then precipitated by the addition of acetone. The precipitate was isolated by filtration, washed with water and then dried to provide 1-(2-chloroethyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride. Analysis: Calculated for C15H18ClN4: % C, 52.80; % H, 5.32; % N, 16.42; Found: % C, 52.67; % H, 5.21; % N, 16.29.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.CN(C)[CH:14]=[O:15].N1(C2[CH2:27][CH2:26][S:25][CH2:24][CH:23]=2)CCCC1>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][CH:23]2[C:14](=[O:15])[CH2:27][CH2:26][S:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: C1=C(N2CCCC2)CCSC1
Solvent: O
Product: O=C(CC1CSCCC1=O)c1ccc(Cl)cc1

Procedure:
A solution of 23.4 g (0.10 mole) of p-chlorophenacyl bromide in 50 ml. of dimethylformamide is added dropwise under nitrogen to a stirred solution of 16.9 g (0.10 mole) of 5,6-dihydro-4-(1-pyrrolidinyl)-2H-thiopyran [Example 1 (a)] and 100 ml. of dimethylformamide. After 6 hours at ambient temperature the mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with water, dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel and eluted with benzene and chloroform mixtures to give an oil which solidifies. The resulting solid is recrystallized from ethanol to give off-white crystals of 3-(4-chlorophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one, m.p. 78° to 81°C.
Reaction SMILES: [OH2:1].[OH2:2].[C:3]1([CH3:12])[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Na+].[C:14]1(S(Cl)(=O)=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>O>[C:22]1([C:5]2[CH:4]=[C:3]([CH3:12])[CH:8]=[CH:7][C:6]=2[S:9](=[O:11])(=[O:10])[S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:12])=[CH:4][C:5]=2[C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)(=[O:2])=[O:1])[C:23]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)S(=O)(=O)c2ccc(C)cc2-c2cccc3ccccc23)c(-c2cccc3ccccc23)c1
Yield: 46.3 %

Procedure:
11.8 g of sodium p-toluenesulfinate dihydrate were dissolved in 20 ml of water, and 11.3 g of α-naphthalenesulfonic acid chloride were added thereto and reacted for 24 hours at room temperature while stirring. 250 ml of water were added thereto, the precipitate formed were taken out by filtration, and this was recrystallized from a mixed solvent comprising benzene and ethanol. Thus, 6.5 g of α-naphthyl-p-methylphenyldisulfone (PAG 5-6) were obtained.
Reaction SMILES: Cl.Cl.[N:3]1([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4]1.[F:15][C:16]([F:31])([F:30])[C:17]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20]>>[N:3]1([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[NH:14][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:28])[F:29])=[CH:25][C:17]=2[C:16]([F:15])([F:30])[F:31])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Agent: Cl
Product: O=C(NC1CCCCC1N1CCCC1)c1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
The title compound, white solid, MS: m/e=409.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride (intermediate F) and 2,4-bis(trifluoromethyl)benzoic acid.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[C:13][C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2ncn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 4-difluoromethyl-8-ethynyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.31) (190 mg, 0.56 mmol) and commercially available 4-bromo-benzenesulfonamide (133 mg, 0.56 mmol) according to general procedure II. Obtained as a brown solid (184 mg, 66%). MS (ISN) 491.2 [(M−H)−]; mp 282° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.C(N(C(C)C)CC)(C)C.Cl.[N:35]1([CH:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:55]=[CH:54][C:50](C(O)=O)=[CH:49][CH:48]=3)[CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.[CH3:56][N:57]([CH3:60])[CH:58]=[O:59]>>[CH3:56][N:57]([CH:60]1[CH2:15][CH2:16][CH2:11][CH2:12][N:13]1[CH3:14])[C:58](=[O:59])[C:50]1[CH:49]=[CH:48][C:47]([N:44]2[CH2:43][CH2:42][CH:41]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH2:46][CH2:45]2)=[CH:55][CH:54]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(N2CCC(N3CCCCC3)CC2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCCCC1N(C)C(=O)c1ccc(N2CCC(N3CCCCC3)CC2)cc1
Reaction time: 14 h
Yield: 44 %

Procedure:
At room temperature, 1-methyl(4-methylamino)piperidine (0.056 ml, 0.38 mmols), O-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (121 mg, 0.32 mmols) and diisopropylethylamine (0.17 ml, 0.96 mmols) were added to a dimethylformamide solution (1.0 ml) of 4-[(4-piperidin-1-yl)piperidin-1-yl]benzoic acid hydrochloride (103 mg, 0.32 mmols) obtained in Reference Example 1, and s in a nitrogen atmosphere at room temperature for 14 hours. The reaction solution was extracted with ethyl acetate, the organic layer was washed with water, saturated sodium bicarbonate solution and saturated saline solution in the order, dried with anhydrous magnesium sulfate, and then concentrated. The residue was purified through preparative thin-layer chromatography (chloroform/methanol/aqueous ammonia=10/1/0.1) to obtain the entitled compound (56 mg, 44%).
Reaction SMILES: [C:1]1([CH:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][NH:35][CH3:36])[CH3:31].C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O>[CH2:30]([O:32][C:33](=[O:37])[CH2:34][N:35]([CH3:36])[CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[CH:14][CH:13]=1)[CH3:31]
Reactant: FC(F)(F)c1cccc(Oc2ccc(OC(CCCl)c3ccccc3)cc2)c1
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)CN(C)CCC(Oc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)c1ccccc1
Temperature: 92.5 °C
Yield: 42.7 %

Procedure:
To a 125 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 486 mg (1.20 mmol) 3-phenyl-3-[4-(3-trifluoromethyl-phenoxy)-phenoxy]-1-chloropropane, 184 mg (1.20 mmol) sarcosine ethyl ester hydrochloride, 0.416 mL (2.40 mmol) diisopropylethylamine, and 6 mL dry N-methylpyrrolidinone. The reaction was heated at 90-95° C. for 60 h, cooled, and poured into water. After extracting with ethyl acetate, the organic layer was washed with water (3 times) and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/methanol as eluant to afford 250 mg (43%) of an oil.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[S:15][C:16](=[C:22]([CH3:24])[CH3:23])[CH2:17][CH2:18][C:19]=2[CH:20]=O)=[CH:9][CH:8]=1.C(N(CC)CC)C.CS([Cl:36])(=O)=O>O>[Cl:36]/[CH:20]=[C:19]1/[C:14](=[N:13]/[C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)/[S:15][C:16](=[C:22]([CH3:24])[CH3:23])[CH2:17][CH2:18]/1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)=C1CCC(C=O)=C(Nc2ccc(Cl)cc2)S1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=C1CCC(=C\Cl)/C(=N/c2ccc(Cl)cc2)S1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an N,N-dimethylformamide (10 ml) solution of 2-(4-chloro-phenylamino)-6-isopropylidene-5,6-dihydro-4H-thiopyran-3-carbaldehyde (0.44 g), triethylamine (0.23 g) and methanesulfonyl chloride (0.24 g) were added at 0° C. After raising the temperature to room temperature and further stirring for 1 hour, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to obtain a crude product of {3-[1-chloro-(E)-methylidene]-6-isopropylidene-tetrahydro-thiopyran-(2Z)-ylidene}-(4-chloro-phenyl)-amine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([C:17]([NH2:19])=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.O.ClCCl>C1COCC1>[NH2:19][CH2:17][CH:14]1[CH2:15][CH2:16][C:11]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:12][CH2:13]1
Reactant: NC(=O)C1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: NCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 1.4 g (0.037 mole) of lithium aluminum hydride in 100 ml dry THF is added, portionwise, 4.9 g (0.026 mole) of 1,4-dioxaspiro[4,5]decane-8-carboxamide over one-half hour. This mixture is then refluxed 2 hours, then allowed to cool to room temperature. About 5 ml water is added cautiously and then stirred 15 minutes. Dichloromethane is then added and the insolubles filtered off. The organic layer is dried over MgSO4 and stripped to dryness, giving 3.48 g crude product. This material is vacuum-distilled to obtain 8-aminomethyl-1,4-dioxaspiro[4,5]decane (b.p. 84°-101° C. at 0.7 mm Hg.)
Reaction SMILES: Cl.Br[CH2:3][C:4]([C:6]1[CH:26]=[CH:25][C:9]2[N:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[N:12][C:8]=2[CH:7]=1)=O.N1C=CC=CC=1.[NH:33]([C:35](=[S:39])[O:36]CC)[NH2:34].O>C(O)C>[CH2:21]([N:10]1[C:9]2[CH:25]=[CH:26][C:6]([C:4]3[CH2:3][S:39][C:35](=[O:36])[NH:33][N:34]=3)=[CH:7][C:8]=2[N:12]=[C:11]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: COc1cccc(-c2nc3cc(C(=O)CBr)ccc3n2CC(C)C)c1
Reactant: CCOC(=S)NN
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: COc1cccc(-c2nc3cc(C4=NNC(=O)SC4)ccc3n2CC(C)C)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 24 g (54.8 mM) of 2-bromo-1-[1-isobutyl-2-(3-methoxyphenyl)-1H-benzimidazol-5-yl]ethanone hydrochloride in 500 ml of ethanol are added 6.3 ml (78.4 mM) of pyridine and then 8.2 g (78.4 mM) of O-ethyl hydrazinecarbothioate. The reaction medium is then maintained at 80° C. with stirring for 20 hours. Water is then added and the resulting mixture is extracted with ethyl acetate. The organic phase is washed with water and then dried over anhydrous sodium sulfate and evaporated under vacuum. The residue is purified on a column of silica, using a dichloromethane/methanol mixture (98/2). The residue obtained after evaporation is taken up in diethyl ether to give, after filtration, 10 g of 5-[1-isobutyl-2-(3-methoxyphenyl)-1H-benzimidazol-5-yl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in the form of a light-beige solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]([OH:16])=O)[CH:10]=2)=[C:5]([F:17])[CH:4]=1)#[N:2].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][CH:32]2[CH2:34][CH2:33]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([N:31]([C:14]([C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[F:17])[O:13][N:12]=2)=[O:16])[CH:32]2[CH2:33][CH2:34]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: N#Cc1ccc(-c2cc(C(=O)O)no2)c(F)c1
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cc(-c3ccc(C#N)cc3F)on2)C2CC2)CC1

Procedure:
The title compound is prepared from 5-(4-cyano-2-fluoro-phenyl)-isoxazole-3-carboxylic acid and 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=1.69 min; Mass spectrum (ESI−): m/z=453 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][C:5]=3[N:6]([CH2:11][C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[C:7]=2[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]2[C:4]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:5]=3[N:6]([CH2:11][C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)COC(=O)Cn1c2c(c3c(Br)cccc31)CCN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)COC(=O)Cn1c2c(c3c(Br)cccc31)CCNCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.8 %

Procedure:
tert-butyl 10-bromo-6-(2-isobutoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0412 g, 0.0859 mmol) was dissolved in CH2Cl2 (2 mL) and trifluoroacetic acid (1.0 mL, 1.48 g, 13.0 mmol, 151 equiv.) was added. The resulting solution was stirred at rt for 2.5 h. The reaction mixture was concentrated to dryness. The residue was taken up in EtOAc (2 mL), then treated with 1N HCl in Et2O. Hydrochloride salt formation did not occur and the resulting solution were concentrated to dryness. The residue was partitioned between EtOAc and 1N NaOH. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude isobutyl (10-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetate (0.0260 g) was obtained in 80% yield. 1H NMR (300 MHz, CD3OD) δ 0.85, 1.86, 2.98-3.03, 3.11-3.14, 3.53-3.56, 3.91, 5.02, 6.94, 7.18, 7.25; MS (ESI+) for C18H23BrN2O2 m/z 379.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](=[O:6])[CH2:4][CH3:5].C[Si]([C:13]#[N:14])(C)C.[N-:15]=[N+:16]=[N-:17].[Na+]>[Cl-].[Zn+2].[Cl-].O>[F:1][C:2]([F:8])([F:7])[C:3]([C:13]1[N:14]=[N:15][NH:16][N:17]=1)([OH:6])[CH2:4][CH3:5]
Reactant: CCC(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Reactant: C[Si](C)(C)C#N
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Product: CCC(O)(c1nn[nH]n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1,1,1-trifluorobutan-2-one (5.0 g, 39.7 mmol, 1.0 equiv) was slowly added trimethylsilylcyanide (4.7 g, 47.6 mmol, 1.2 equiv) and the resulting mixture stirred overnight at ambient temperature. To the resulting mixture was added water (80 mL) followed by zinc chloride (5.4 g, 39.7 mmol, 1.0 equiv) and sodium azide (3.1 g, 47.1 mmol, 1.2 equiv) and the mixture was heated at 80° C. for three hours. The mixture was cooled to room temperature and the precipitate was filtered and dried in vacuo to afford 1,1,1-trifluoro-2-(2H-tetrazol-5-yl)butan-2-ol (3-3) as a white solid. LRMS m/z (M+H)+ 197.0 found, 197.1 required.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:17]1([CH2:16][N:14]([CH3:15])[C:12]2[C:11]([C:20]([F:21])([F:23])[F:22])=[CH:10][C:9]3[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:18][CH2:19]1
Reactant: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CC1CC1)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
The title compound was prepared from [2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-(cyclopropylmethyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M68) (173 mg, 0.33 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (81 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](CC#N)[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.NN.[ClH:31].O>C(O)C>[ClH:31].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[CH:4][CH:3]=1
Reactant: N#CCN1CCC(c2nc(COCC(F)(F)F)c(-c3ccc(F)cc3)o2)CC1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2oc(C3CCNCC3)nc2COCC(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 90.1 %

Procedure:
A 5-l round bottom flask containing {4-[5-(4-fluorophenyl)-4-(2,2,2-trifluoro-ethoxymethyl)-oxazol-2-yl]-piperidin-1-yl} acetonitrile (313 g, 0.788 mole), 35% aqueous hydrazine (156 mL, 1.58 mole), 36% aqueous hydrochloric acid (130 mL, 1.58 mole), water (1 l) and ethanol (2 l) is warmed to 75° C. and stirred for 3.5 hours. The reaction mixture is cooled to room temperature, the solvent volume is reduced to 1.5 l by distillation and 3 N aqueous hydrochloric acid (1.5 l) is added. The aqueous solution is washed with dichloromethane (2×3 l). The combined organic extracts are dried over sodium sulfate (1 Kg), filtered and concentrated to effect crystallization (1.5 l). To complete the crystallization, methyl t-butylether (4 l) is added and the resulting slurry is cooled to 0° C. The solids are collected by filtration, washed with methyl t-butylether (750 mL) and dried to constant weight to give {4-[5-(4-fluorophenyl)-4-(2,2,2-trifluoro-ethoxymethyl)-oxazol-2-yl]-piperidine hydrochloride (280 g, 0.710 mole). 1H NMR (400 MHz, d6 DMSO) d 1.96 (m, 2H), 2.20 (m, 2H), 3.02 (q, 2H), 3.30 (m, 3H), 4.18 (q, 2H), 4.66 (s, 2H), 7.37 (t, 2H), 7.68 (q, 2H), 9.0 (bs, 1H), 9.20 (bs, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Cl:18]Cl>C(O)(=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([S:11]([C:14]([F:17])([F:15])[F:16])(=[O:13])=[O:12])[CH:8]=[C:7]([Cl:18])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]
Reactant: ClCl
Solvent: CC(=O)O
Product: Nc1c(Cl)cc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]
Yield: 95.3 %

Procedure:
In analogy to Example 14, 27 g of 2-nitro-4-trifluoromethylsulphonyl-aniline in 100 ml of acetic acid were chlorinated with 10 g of chlorine. 29 g of 2-nitro4-trifluoromethylsulphonyl-6-chloro-aniline were obtained; melting point 138°-139° C.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:3]([CH3:19])[C:4]([N:6]1[C@H:10]([CH3:11])[C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][C:7]1=[O:18])=[O:5].[CH3:32]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+](C)C>ClCCl>[CH3:32][O:1][C@@H:2]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C@@H:3]([CH3:19])[C:4]([N:6]1[C@H:10]([CH3:11])[C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][C:7]1=[O:18])=[O:5]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](C)[C@@H](O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CO[C@H]([C@@H](C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
Following a literature method (Diem, M. J.; Burow, D. F.; Fry, J. L. Journal of Organic Chemistry 42(10), 1977, 1801-1802), to a solution of tert-butyl (2S)-2-{(1R,2R)-1-hydroxy-2-methyl-3-[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]-3-oxopropyl}pyrrolidine-1-carboxylate (0.70 g, 1.6 mmol, from Reference Example 5) in anhydrous dichloromethane (5 mL) is added N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (0.62 g, 2.9 mmol), followed by trimethyloxonium tetrafluoroborate (0.35 g, 2.4 mmol). The resulting reaction mixture is stirred for 24 hours at room temperature, quenched by the addition of ice water (25 mL), and then filtered through a diatomaceous earth pad. The filtrate is evaporated under reduced pressure and then partitioned between diethyl ether and water. The aqueous phase is extracted thrice with diethyl ether. The combined organic extracts are washed with 1 M aqueous potassium bisulfate solution, water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.69 g (97%) of tert-butyl (2S)-2-{(1R,2R)-1-methoxy-2-methyl-3-[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]-3-oxopropyl}pyrrolidine-1-carboxylate as a foam.