Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:27][CH2:26][C:21]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:20][CH2:19]3)=[C:14]([CH3:28])[CH:13]=2)[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[NH2:29][C@@H:30]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]1.CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:29][C@@H:30]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]2)=[N:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][CH2:19]2)=[C:14]([CH3:28])[CH:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: Cc1cc(Nc2nc(Cl)cnc2C(N)=O)ccc1N1CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)cnc2C(N)=O)ccc1N1CCC2(CC1)OCCO2

Procedure:
A mixture of 5-chloro-3-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-methylphenyl]amino}pyrazine-2-carboxamide (1.7 g), tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (3.57 mL), and N-methylpyrrolidone (10.8 mL) was reacted in a microwave reaction device at 190° C. for 60 minutes. The reactant was left to be cooled, and then water and a saturated aqueous sodium hydrogen carbonate solution were added thereto, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-500:10:1) to obtain tert-butyl (3R)-3-[(5-carbamoyl-6-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-methylphenyl]amino}pyrazin-2-yl)amino]pyrrolidine-1-carboxylate (1.71 g) as a yellow amorphous substance.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:18])[CH:24]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
Reactant: OB(O)c1cccc(Cl)c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2cccc(Cl)c2)o1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3-chlorophenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M in diethyl ether) was added and the solution was evaporated. After drying under vacuum, the hydrochloride salt of the title compound was obtained as a colourless solid; MS (ES+) 331 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:32])=[C:24]([CH2:27][CH2:28][C:29]([OH:31])=O)[CH:25]=2)[NH:20][C:19](=[O:33])[C:18]=1[C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[CH:35]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)[CH2:45][CH2:46][CH2:47][N:48]=[C:49]=NCC.ON1C2C=CC=CC=2N=N1.N1CCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:32])=[C:24]([CH2:27][CH2:28][C:29](=[O:31])[N:48]3[CH2:49][CH2:45][CH2:46][CH2:47]3)[CH:25]=2)[NH:20][C:19](=[O:33])[C:18]=1[C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[CH:35]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CCC(=O)O)c(Cl)cc3[nH]c2=O)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCNC1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CCC(=O)N4CCCC4)c(Cl)cc3[nH]c2=O)c1
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a solution of 2-{2-[6-(2-carboxyethyl)-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (15 mg in 0.5 mL of dry methylene chloride) was added 8.0 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) followed by 5.2 mg 1-hydroxybenzotriazole (HOBt) and the mixture stirred for 10 minutes. At this time, 9.2 mg of pyrrolidine was added and the reaction allowed to proceed at room temperature. After 40 minutes, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride: 10% ammonium hydroxide in methanol, 95:5; then 90:10) to give the title compound (9 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:23]=[C:24]([C:26]3[O:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH:5]=[C:6]([C:8]#[C:9][C:10]([CH3:22])([OH:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[N:7]=1.O.O.Cl[Sn]Cl>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:4]([N:23]=[C:24]([C:26]3[O:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH:5]=[C:6]([C:8]#[C:9][C:10]([CH3:22])([OH:21])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[N:7]=1
Reactant: CC(O)(C#Cc1cn2nc(-c3ccco3)nc2c(N)n1)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)(C#Cc1cn2nc(-c3ccco3)nc2c(N)n1)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a solution of 4-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-2-methyl-1-(4-nitro-phenyl)-but-3-yn-2-ol-(17.7 mg, 0.044 mmol;. see Ex. 72 below which was prepared according to Example 24 above) in DMF (3 mL) was added SnCl2.2H2O (98 mg, 0.43 mmol) and the reaction was stirred at room temperature for overnight. The solvent was removed in vacuo and the residue was purified by reversed phase HPLC eluting with a water/acetonitrile gradient to yield the title compound (6.5 mg, 39%) as yellow solid. 1H NMR (300 MHz, DMSO) δ 8.25 (s, 1H), 7.93 (br s, 1 H), 7.60 (s, 2H), 7.33 (m, 2H), 7.14 (br s, 1H), 7.04 (m, 2H), 6.72 (br s, 1H), 2.82 (s, 2H), 1.38 (s,3 H). MS: m/z=375 amu (M++H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](Cl)=[N:16][OH:17].[CH2:19]([OH:22])[C:20]#[CH:21]>C(OCC)C>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:21]=[C:20]([CH2:19][OH:22])[O:17][N:16]=1
Reactant: ON=C(Cl)c1ccccc1Cl
Reactant: C#CCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: OCc1cc(-c2ccccc2Cl)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of triethylamine (48 mL) in diethyl ether (0.5 L) was added over two hours to a 0° C. solution of the compound prepared in Example 5 (50.0 g) and propargyl alcohol (31 mL) in diethyl ether (1.2 L). The reaction was stirred at room temperature overnight, washed with water, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (50.0 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][O:9]1.[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:23][C:20]1[N:12]2[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[O:9][CH2:10][C:11]2=[N:22][N:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)OCc1nncn1-2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)OCc1nnc(Br)n1-2
Yield: 36.4 %

Procedure:
A suspension of Compound 9 prepared in Example 4-(1) (1.2 g), N-bromosuccinimide (0.675 g), and α,α'-azobis-isobutyronitrile (10 mg) in carbon tetrachloride (70 ml) is refluxed under heating for 1 hour. The insoluble materials are removed by filtration and the solvent is evaporated. The residue is treated on column chromatography (silica gel/ethyl acetate) to give the title compound (0.54 g), which is recrystallized from ethyl acetate. Yield 36.4%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:18]([C:19]=2[CH2:20][CH:21]=1)[CH2:17][CH2:16][C@@:13]1([CH2:14][CH3:15])[C@H:9]3[CH:10]=[CH:11][C@@H:12]1[OH:22].C(O)(C)(C)C>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][C@@H:8]3[C@@H:18]([C:19]=2[CH2:20][CH:21]=1)[CH2:17][CH2:16][C@@:13]1([CH2:14][CH3:15])[C@H:9]3[CH:10]=[CH:11][C:12]1=[O:22]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1C=C[C@@H]2O)CC(OC)=CC4
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1C=CC2=O)CC(OC)=CC4

Procedure:
4.7 g of 3-methoxy-18-methyl-2,5(10),15-estratrien-17β-ol is refluxed for 18 hours in 250 ml of chloroform and 35 ml of t-butanol with 10 g of manganese dioxide. The product is suctioned off over Celite, rewashed with chloroform and concentrated under reduced pressure. After chromatographic purification on silica gel with hexane/ethyl acetate, 4.1 g of pure 3-methoxy-18-methyl-2,5(10),15-estratrien-17-one with a melting point of 89°-91° C. is obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[C:7]([CH3:13])[CH:6]=1)(=[O:3])[CH3:2].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:13])[C:8]([Br:12])=[C:9]([CH2:11][Br:14])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C)c(Br)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(C)c(Br)c(CBr)c1
Temperature: 75 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
A suspension of 4-bromo-3,5-dimethylphenyl acetate (12.1 g, 49.8 mmol), N-bromosuccinimide (9.79 g, 55.0 mmol) and 2,2′-azobisisobutyronitrile (82.1 mg, 0.500 mmol) in carbon tetrachloride (100 mL) was stirred at 75° C. for 5 hr under nitrogen atmosphere. The reaction mixture was ice-cooled, and concentrated under reduced pressure. The residue was diluted with diethyl ether, the insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was-purified by silica gel column chromatography (ethyl acetate:hexane=0:100-25:75) to give the title compound (11.7 g, yield 73%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([Cl:13])[CH:3]=1.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1.[Cl-].[Na+].O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([Cl:13])[CH:3]=1)(=[O:24])[CH3:23]
Reactant: CON(C)C(C)=O
Reactant: CC(C)(C#N)c1ccc(Br)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(C(C)(C)C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
To a stirred solution of 2-(4-bromo-2-chlorophenyl)-2-methylpropanenitrile (2.85 g, 11.0 mmol) in anhydrous THF (60 mL) at −78° C. is added n-butyllithium (2 M in c-hexane) (6.1 mL, 12.1 mmol). The reaction mixture is stirred at this temperature 10 min., then N-methoxy-N-methyl-acetamide (2.34 mL, 22.0 mmol) is added neat and the solution is stirred 10 min. at −78° C. and then warmed up to room temperature for another hour. Acidic brine (60 mL) is then slowly added and the solution is extracted with EtOAc (3×60 mL). The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (eluent: Hex/EtOAc 1:0 to 7:3) to provide the expected product 2-(4-acetyl-2-chlorophenyl)-2-methylpropanenitrile (1.57 g, 64%) as a yellow oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.96 (1H, d, J=1.9 Hz), 7.81 (1H, dd, J=8.3, 1.9 Hz), 7.55 (1H, d, J=8.3 Hz), 2.56 (3H, s), 1.85 (6H, s).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].[OH-:16].[K+:17]>O>[F:1][C:2]1[C:7]([S:8]([O-:16])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].[K+:17]
Reactant: [OH-]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Agent: [K+]
Solvent: O
Product: O=S(=O)([O-])c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
A mixture of pentafluorobenzenesulfonyl chloride (25.0 g, 94 mmoles) and potassium hydroxide (86% purity, 12.3 g, 188 mmoles) was dissolved in 230 ml water and stirred at room temperature for 18 hours. The produced precipitate was filtered off and recrystallized from water (about 6 ml/g product). Colorless needles formed were filtered, washed with cool water and ethanol and dried in a vacuum oven for 24 hours to yield 22.1 g of potassium pentafluorobenzene sulfonate (82% yield).
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([N:16]2[CH2:8][CH2:7][CH:2]2[C:3]([O:5][CH3:6])=[O:4])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCCC1
Reactant: COC(=O)C(Br)CCBr
Product: COC(=O)C1CCN1C1CCCCC1
Yield: 76 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with cyclohexylamine 18A yielded methyl 1-(cyclohexyl)azetidine-2-carboxylate as a brown oil (76%). MS ISP (m/e): 198.2 (100) [(M+H)]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]1)[C:6](=[O:26])[C:5]12OCC[O:27]1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]1)[C:6](=[O:26])[C:5]2=[O:27]
Reactant: Cc1ccc2c(c1)C1(OCCO1)C(=O)N2CCC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(=O)C(=O)N2CCC1CCN(Cc2ccccc2)CC1

Procedure:
The compound of Example 101 (850 mg) in tetrahydrofuran (30 ml) was treated with 3M hydrochloric acid (17 ml). The mixture was heated under reflux overnight, then cooled, and neutralised by the addition of aqueous sodium bicarbonate. The mixture was extracted with dichloromethane. The extracts were washed, dried and evaporated and the residue was purified by flash chromatography to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28]>O1CCOCC1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:31]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:32])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: CC(C)N=C=O
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)NC(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxan (0.5 mL) and isopropyl isocyanate (0.012 mL, 0.12 mmol) was added. The solution was stirred at 50° C. for 24 h. Isopropyl isocyanate (0.006 mL, 0.06 mmol) was added. The solution was stirred at 50° C. for 24 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.4, 160.9 (dd), 157.8 (dd), 157.4, 151.1, 140.9, 138.7, 136.1, 134.9, 132.6, 131.9, 128.7, 127.3 (dd), 125.9 (dd), 122.4, 120.7, 116.6, 112.9, 112.6 (dd), 105.7 (dd), 42.8, 23.4, 19.6
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][C:3]=1[F:19].[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].O>CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[F:19])[CH2:6][C:7]1([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]1)[C:8]2=[N:26][S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25]
Reactant: CC(C)(C)S(N)=O
Reactant: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=NS(=O)C(C)(C)C
Temperature: 25 °C
Yield: 57 %

Procedure:
6′-Bromo-5′-fluoro-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 8, 2.0 g, 6.11 mmol), 2-methylpropane-2-sulfinamide (1.11 g, 9.17 mmol) and titanium ethoxide (2.52 mL, 12.2 mmol) were dissolved in 2-Me THF (31 mL) and heated to reflux for 48 h. The reaction was allowed to cool to r.t. whereafter it was diluted with EtOAc (75 mL). Water (25 mL) was added dropwise over 10 min under vigorous stirring and then the mixture was left standing without stirring for 1.5 h. The solids were filtered off and the organics were concentrated. The was purified by silica gel chromatography using a stepwise gradient of heptane/EtOAC (5:1-4:1-3:1-1:1), to give the title compound (1.5 g, 57% yield) as a diasteromer mixture in the ratio ˜4:1 (established by HPLC and NMR analysis) (1.50 g, 57% yield). The was used in the next step. 1H NMR (500 MHz, CDCl3, signals for both isomers) δ ppm 1.20-1.29 (m, 1 H) 1.30-1.41 (m, 14 H) 1.50-1.60 (m, 4 H) 1.60-1.68 (m, 1 H) 1.97-2.08 (m, 1 H) 2.08-2.20 (m, 2.5 H) 2.24-2.32 (m, 0.3 H) 2.95-3.02 (m, 2.5 H) 3.22-3.32 (m, 1 H) 3.35 (s, 0.9 H) 3.40 (s, 3 H) 3.48-3.53 (m, 0.3 H) 7.09-7.11 (m, 0.3 H) 7.13 (d, 1 H) 8.64-8.88 (m, 1 H); MS (ES+) m/z 430, 432 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1.[C-:17]#[N:18].[Na+].C(OCC)(=O)C>CS(C)=O>[N:15]1[C:9]2[NH:8][C:7]3[CH:16]=[C:3]([CH2:2][C:17]#[N:18])[CH:4]=[CH:5][C:6]=3[S:11][C:10]=2[N:12]=[CH:13][CH:14]=1
Reactant: ClCc1ccc2c(c1)Nc1nccnc1S2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)Nc1nccnc1S2
Yield: 104.2 %

Procedure:
To 50 ml of a solution of 5 g of 8-(chloromethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine in dimethyl sulfoxide was added 0.92 g of sodium cyanide and the resulting mixture was reacted at 60° C. for 1 hour. After adding ethyl acetate, the organic layer was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 4.7 g of the title compound was obtained as a yellow solid.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])([CH3:8])[CH3:7].[F:19][C:20]1[CH:25]=[C:24](F)[CH:23]=[C:22]([F:27])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:19][C:20]1[CH:25]=[C:24]([N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][C:6]([CH3:5])([CH3:7])[CH3:8])[CH2:18][CH2:17]2)[CH:23]=[C:22]([F:27])[CH:21]=1
Reactant: Fc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(F)cc(F)c2)CC1
Temperature: 100 °C
Yield: 73 %

Procedure:
A DMSO (25 mL, 0.1M) solution containing 4-N—BOC-aminopiperidine (500 mg, 2.5 mmol, 1.0 eq), 1,3,5-trifluorobenzene (256 μL, 2.5 mmol, 1.0 eq), and potassium carbonate (691 mg, 5.0 mmol, 2.0 eq) was heated to 100° C. for 18 h. The resulting mixture was cooled to RT, poured in H2O (ca 50 mL), and extracted (3×) with EtOAc. The combined extracts were washed (2×) with H2O, dried over MgSO4, and concentrated in vocuo. The resulting solid was purified via flash chromatography using 1:1 Hexane/EtOAc as the mobile phase. Isolated 572 mg (1.83 mmol, 73% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[S:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=O>[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Cl-].[Zn+2]>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=2[N:10]=[C:14]2[CH2:15][CH2:16][S:11][CH2:12][C:13]=12
Reactant: N#Cc1ccc(F)cc1N
Reactant: O=c1ccccs1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=[N+]([O-])c1ccccc1
Product: Nc1c2c(nc3cc(F)ccc13)CCSC2
Temperature: 50 °C
Yield: 62.4 %

Procedure:
A mixture of 4-fluoroanthranilonitrile (4.47 g) and freshly fused, pulverized ZnCl2 (6.7 g) in 20 ml of nitrobenzene was heated at 50° C. for 45 minutes. To the resulting suspension was added thiopyran-2-one (5.1 g). This was heated at 130° C. for 3 hours. The resulting precipitate was filtered, rinsed with ether and partioned between 2-butanone and NH4OH solution. The aqueous layer was extracted with 2-butanone and the combined organics were washed with water and dried (MgSO4). This resulted in 4.8 g of a tan solid, m.p. 234°-237° C. d., which was recrystallized from ethyl acetate to give 3.0 g of a white powder, m.p. 235°-237° C. d.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=3)[N:19]([CH2:27][CH2:28][CH2:29][CH3:30])[C:18]=2[CH3:31])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:32]>CO.C(O)C.[C].[Pd]>[ClH:32].[CH2:27]([N:19]1[C:20]2[C:25](=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:17]([C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:16])=[C:18]1[CH3:31])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCn1c(C)c(C(=O)NC2CCN(Cc3ccccc3)CC2)c2cc(O)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCCCn1c(C)c(C(=O)NC2CCNCC2)c2cc(O)ccc21
Reaction time: 6 h

Procedure:
To a solution of 9 g of N-(1-benzyl-4-piperidyl)-1-butyl-5-hydroxy-2-methylindole-3-carboxamide in 100 ml of methanol were added 5 g of an 18% hydrochloric acid in ethanol and 4 g of 10% palladium carbon, and the mixture was subjected to catalytic hydrogenation at atmospheric pressure for 6 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The residue was crystallized with ethyl acetate and the resulting crystals were recrystallized from ethanol to give 4 g of 1-butyl-5-hydroxy-2-methyl-N-(4-piperidyl)indole-3-carboxamide hydrochloride, melting at 164°-168° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.[Br:16][C:17]1[CH:18]=[C:19]([F:24])[C:20](F)=[N:21][CH:22]=1.Cl>CS(C)=O.O>[Br:16][C:17]1[CH:18]=[C:19]([F:24])[C:20]([O:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)=[N:21][CH:22]=1
Reactant: Fc1cc(Br)cnc1F
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ncc(Br)cc2F)cc1)C(=O)O
Reaction time: 0.33 h

Procedure:
A solution of NaOH (0.54 g, 0.013 mol) in a few ml of water was added to 2-(4-hydroxyphenoxy)propionic acid (1.22 g, 0.0067 mol) in 20 ml DMSO and the mixture was stirred for 20 minutes under N2. 5-Bromo-2,3-difluoropyridine (1.3 g, 0.0067 mol) was added and the mixture was stirred for 51/2 hours at 80°-90° C. The reaction mixture was poured into water, acidified with concentrated HCl to pH 1 and extracted into CH2Cl2. The solution was dried over Na2SO4 and the solvent was removed by rotary evaporation to yield a gum which became an off-white solid (0.78 g, 33%, m.p. 94°-97° C.) upon standing.