Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C(C(F)(F)F)=CC=C2C=1C=NC=C2.[F:16][C:17]1[C:18]([C:27]([F:30])([F:29])[F:28])=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]=[N:24][CH:23]=[CH:22]2>>[F:16][C:17]1[C:18]([C:27]([F:30])([F:28])[F:29])=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][NH:24][CH2:23][CH2:22]2
Reactant: Fc1c(C(F)(F)F)ccc2ccncc12
Agent: Nc1c(C(F)(F)F)ccc2ccncc12
Product: Fc1c(C(F)(F)F)ccc2c1CNCC2

Procedure:
By the procedure of Example 16, 8-amino-7-trifluoromethylisoquinoline is converted to 8-fluoro-7-trifluoromethylisoquinoline. Hydrogenating by the procedure of Example 9 gives 8-fluoro-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]1([C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[N:3]=[C:4]([C:9]3[N:10]([CH2:18][CH3:19])[C:11]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=4[N:17]=3)[C:5]([NH2:8])=[N:6][CH:7]=2)[CH:21]=1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3cccc(-c4ccccc4)c3)cnc2N)nc2cnccc21
Temperature: 200 °C
Yield: 5.4 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), 3-phenylbenzeneboronic acid (0.040 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes. The reaction mixture was concentrated in vacuo and the residue purified by mass directed HPLC to give 0.0021 g of the title compound.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7](=[O:10])(O)[O-:8].[Na+]>C(Cl)Cl.CCOCC>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:8][CH:7]1[CH2:5][CH2:4][CH2:3][CH2:2][O:10]1
Reactant: O=C([O-])O
Reactant: C1=COCCC1
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C1CCC(OC2CCCCO2)OC1

Procedure:
A solution of 1.15 g of the ketone, 1.2 ml of dihydropyran and 10 mg of p-toluolsulfonic acid in 40 ml of methylene chloride is stirred for 30 minutes at 0° C. The product is then diluted with ether, shaken with dilute sodium bicarbonate solution, washed with neutral water, dried via magnesium sulfate and concentrated by evaporation in a vacuum. 1.65 g of the bis-tetrahydropyranyl ether is obtained, which is used without any further purification.
Reaction SMILES: C([Mg]Br)(C)C.[CH2:6]([CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]1=[O:16])[CH3:7].C(NC(C)C)(C)C.C[O:25][C:26]1[CH2:31][CH2:30][CH2:29][C:28](=O)[CH:27]=1.Cl>CCOCC.C1COCC1>[CH2:6]([C:8]1([C:28]2[CH2:29][CH2:30][CH2:31][C:26](=[O:25])[CH:27]=2)[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]1=[O:16])[CH3:7]
Reactant: COC1=CC(=O)CCC1
Reactant: CCC1CCCCN(C)C1=O
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC1(C2=CC(=O)CCC2)CCCCN(C)C1=O
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A 2 molar solution of isopropylmagnesium bromide in ether (70 ml) was treated with 3-ethyl-hexahydro-1-methyl-2H-azepin-2-one (21.7 g, Aust. J. Chem. 1976, 29 2651) in THF (20 ml) and the mixture treated dropwise with diisopropylamine (19.6 ml) (exothermic). The reaction mixture was stirred for 2 hours then treated dropwise with 3-methoxy-2-cyclohexenone (12.6 g) in THF (20 ml). After stirring for 2 hours the reaction mixture was poured onto cold 2 N HCl (250 ml). After 10 minutes the mixture was extracted with dichloromethane (2×300 ml), the combined organic phases washed with saturated aqueous NaHCO3 solution and dried (MgSO4). Removal of the solvents under reduced pressure followed by distillation gave the title compound as a viscous oil (Bpt 155°-160° C./0.1 mm) (13 g). Redistillation (154°-158° C./0.07 mm) gave analytically pure material.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>>[C:14]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)(=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)Cl
Reactant: CC(C)Nc1ccc([N+](=O)[O-])cc1
Product: C=CC(=O)N(c1ccc([N+](=O)[O-])cc1)C(C)C

Procedure:
Prepared from 4-isopropylamino-nitrobenzene and acrylic acid chloride
Reaction SMILES: [C:1]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20]N(C)CCCN=C=NCC.C[O-].[Na+].Cl>CO.O1CCCC1.C(#N)C>[C:1]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([O:18][CH3:20])=[O:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CCCC[C@H]1C(=O)O)c1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CCCC[C@@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
A mixture of (1R,2S)-2-(benzoylamino)cyclohexanecarboxylic acid (2.47 g, 10 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.30 g, 12 mmol), acetonitrile (25 ml) and tetrahydrofuran (25 ml) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, methanol (25 ml) was added, and the mixture was stirred at 60° C. for 3 hrs. The reaction mixture was concentrated under reduced pressure, dil. hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution, then with saturated brine and dried (over anhydrous MgSO4). The solvent was evaporated under reduced pressure. 28% Sodium methoxide in methanol solution (1.93 g, 10 mmol) and methanol (30 ml) were added to the residue and the mixture was heated under reflux for 5 hrs. 1N Hydrochloric acid (11 ml) was added under ice-cooling, and methanol was evaporated under reduced pressure. Aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The obtained solid was collected by filtration and washed with diisopropy ether to give methyl (1S,2S)-2-(benzoylamino)cyclohexanecarboxylate (1.33 g, 51%) as a colorless powder.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:26][C:27]1[N:32]=[CH:31][C:30]([CH2:33][OH:34])=[C:29]([CH:35]=O)[C:28]=1[OH:37].C(N(CC)CC)C>C1COCC1>[CH2:4]([O:3][C:1](=[O:2])[CH:6]=[CH:35][C:29]1[C:30]([CH2:33][OH:34])=[CH:31][N:32]=[C:27]([CH3:26])[C:28]=1[OH:37])[CH3:5]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ncc(CO)c(C=O)c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1c(CO)cnc(C)c1O
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A clear solution of (carbethoxymethylene)triphenylphosphorane (22.3 g, 64.02 mmol) in THF was added to pyridoxal (13.01 g, 64.0 mmol) in THF at room temperature. The mixture was stirred for one hour, then triethylamine (10 mL) was added and the mixture was stirred until the solution turned to a yellow suspension. The solvent was evaporated, and the crude product purified by column chromatography on silica gel using a mixture of dichloromethane:methyl alcohol (20:1) as eluant to give 3-(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-yl)-acrylic acid ethyl ester (34) (15.2 g, quantitative yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH3:9].[CH3:26][N:27]1[CH:31]=[C:30]([CH:32]=O)[CH:29]=[N:28]1.Cl>C(O)C>[CH3:9][N:8]1[C:32]([C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)=[N:1][C:2]2[C:7]1=[N:6][CH:5]=[N:4][C:3]=2[N:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:14][CH2:15]1
Reactant: Cn1cc(C=O)cn1
Reactant: CNc1ncnc(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c1N
Agent: Cl
Solvent: CCO
Product: Cn1cc(-c2nc3c(N4CCC(n5c(=O)[nH]c6ccccc65)CC4)ncnc3n2C)cn1
Temperature: 80 °C
Yield: 72.9 %

Procedure:
To a solution of 1-(1-(5-amino-6-(methylamino)pyrimidin-4-yl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (70 mg, 0.2 mmol) in anhydrous ethanol (8 mL) were added 1-methyl-1H-pyrazole-4-carbaldehyde (34 mg, 0.3 mmol) and catalytic amount of hydrochloric acid (0.05 mL, 4M HCl in Dioxane, Aldrich). The reaction mixture was heated to 80° C. for 18 hours. The resulting precipitate was collected by vacuum filtration, washed with ethanol (2 mL) and dried under reduced pressure, to give 62.6 mg (70% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.13 (dd, 1H), 6.93 (m, 3H), 4.53 (m, 1H), 3.92 (s, 3H), 3.81 (d, 3H), 3.33 (m, 2H), 3.24 (m, 2H), 2.33 (m, 2H), 1.82 (d, 2H); MS (EI) for C22H23N9O: 430.4 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8](/[CH:9]=[CH:10]\[C:11]2[N:19]([CH3:20])[C:18]3[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH3:24])[C:15](=[O:25])[N:14]([CH2:26][CH2:27][CH3:28])[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:20][N:19]1[C:18]2[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH3:24])[C:15](=[O:25])[N:14]([CH2:26][CH2:27][CH3:28])[C:13]=2[N:12]=[C:11]1/[CH:10]=[CH:9]\[C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:30][CH:29]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C\c3ccc(C(=O)OC)cc3)n2C)n(CCC)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCn1c(=O)c2c(nc(/C=C\c3ccc(C(=O)O)cc3)n2C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Compound 8 (2.64 g, 6.44 mmol) obtained in Example 7 was dissolved in a solvent mixture of 60 ml of dioxane and 40 ml of water. To the solution was added 1.08 g (25.8 mmol) of lithium hydroxide monohydrate, and the resulting mixture was stirred at room temperature for one hour. After neutralization with 1N HCl, the mixture was extracted three times with ethyl acetate. The combined extract was dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The resulting crude crystals were recrystallized from toluene/cyclohexane to give 2.26 g (yield 89%) of Compound 18 as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH3:20][N:21]([CH3:37])[CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[O:28][C:29]3[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:30]=3[N:31]=2)[CH2:23]1>>[CH3:20][N:21]([CH3:37])[CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[O:28][C:29]3[CH:35]=[CH:34][C:33]([NH:36][C:9](=[O:11])[CH:8]=[CH:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=4)=[CH:32][C:30]=3[N:31]=2)[CH2:23]1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: CN(C)C1CCN(c2nc3cc(N)ccc3o2)C1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc(C=CC(=O)Nc2ccc3oc(N4CCC(N(C)C)C4)nc3c2)cc1
Yield: 72.2 %

Procedure:
Prepare according to Method C (Example 9), using 4-methoxycinnamic acid (110 mg, 0.617 mmol), oxalyl chloride (300 μL, 3.43 mmol), and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzooxazol-5-ylamine (99 mg, 0.402 mmol) to afford the title compound (118 mg, 72%). mass spectrum (m/e): 407.4 [M+H], 405.3 [M−H].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])[CH3:19])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH:28]=O>CCO.[OH-].[Na+]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])/[CH:19]=[CH:28]/[C:27]2[CH:30]=[CH:31][C:32]([F:33])=[C:25]([F:24])[CH:26]=2)=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1c(C(=O)/C=C/c2ccc(F)c(F)c2)c2cc(O)ccc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
General Procedure G. To a solution of 1-(1-benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)ethanone (Compound 29, 64 mg, 0.21 mmol) in EtOH (3 ml) and NaOH (4 M, 0.53 ml) at room temperature was added 3,4-difluorobenzaldehyde (46 μl, 0.42 mmol). The reaction was stirred for 16 h, heated to 60° C. for 4 h, and more 3,4-difluorobenzaldehyde (180 μl, 1.68 mmol) was added, stirred at room temperature for 24 h. The reaction was quenched by 1 M HCl (5 ml), and stirred at room temperature for 4 h, and the product was extracted with EtOAc. The layers were separated and the organic layer was washed with brine, and dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 0-30% EtOAc-hexanes followed by PTLC (30% EtOAc-hexanes) to yield (E)-1-(1-benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-3-(3,4-difluorophenyl)prop-2-en-1-one (Compound 30) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:9][C:10]1[S:14][C:13]2=[N:15][C:16]([C:18](O)=[O:19])=[CH:17][N:12]2[CH:11]=1>>[Br:9][C:10]1[S:14][C:13]2=[N:15][C:16]([C:18]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=3)=[O:19])=[CH:17][N:12]2[CH:11]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: Nc1cccc(Cl)c1
Product: O=C(Nc1cccc(Cl)c1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLVI, using 3-chloroaniline and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[F:22][C:23]([F:36])([F:35])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:32]1[CH2:33][CH2:34][CH:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:22])([F:35])[F:36])=[CH:25][CH:26]=2)[CH2:31]1)=[O:15]
Reactant: FC(F)(F)c1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(c2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-[4-(trifluoromethyl)phenyl]pyrrolidine oxalate (15.1 mg, 0.050 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (3.8 mg). Calcd for C21H16ClF3N2O2: 420.0852, found 420.0855.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[CH:8][C:9]3[CH2:10][CH2:11][C:12]4[CH:18]=[C:17](OS(C(F)(F)F)(=O)=O)[CH:16]=[CH:15][C:13]=4[C:14]=3[N:6]2[CH2:5][CH2:4][N:3]=1.[Cl-].[Li+].C1(P([C:42]2[CH:47]=[CH:46]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Sn](CCCC)(CCCC)C1CC1)CCC.[C:64]([OH:71])(=[O:70])/[CH:65]=[CH:66]/[C:67]([OH:69])=[O:68]>CN(C)C=O.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl.CO.O>[C:64]([OH:71])(=[O:70])/[CH:65]=[CH:66]/[C:67]([OH:69])=[O:68].[CH:46]1([C:17]2[CH:16]=[CH:15][C:13]3[C:14]4[N:6]5[CH2:5][CH2:4][N:3]=[C:2]([CH3:1])[C:7]5=[CH:8][C:9]=4[CH2:10][CH2:11][C:12]=3[CH:18]=2)[CH2:47][CH2:42]1
Reactant: CC1=NCCn2c1cc1c2-c2ccc(OS(=O)(=O)C(F)(F)F)cc2CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)C1CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CC1=NCCn2c1cc1c2-c2ccc(C3CC3)cc2CC1
Temperature: 120 °C
Yield: 4 %

Procedure:
Trifluoromethanesulphonic acid 5,6,10,11-tetrahydro-8-methyl-benzo[g]pyrazino[1,2-a]indol-3-yl-ester (2.0 g), 1.85 g of anhydrous lithium chloride, 0.44 g of bis(triphenylphosphine)palladium dichloride, 0.88 g of triphenylphosphine and 3.5 g of tri-n-butyl-cyclopropyltin were suspended in 25 ml of dimethylformamide under argon and heated to 120° C. for 6 h. while stirring. The reaction mixture was added to 500 ml of water and extracted once with 200 ml of ethyl acetate and twice with 100 ml of ethyl acetate each time. The ethyl acetate extracts were extracted four times with 2N hydrochloric acid (1×100 ml, 3×50 ml), the aqueous phases were combined, made basic with 120 ml of 28% sodium hydroxide solution and extracted three times with 100 ml of methylene chloride each time. The combined methylene chloride extracts were washed twice with 60 ml of saturated potassium fluoride solution each time and once with 500 ml of water. The organic phase was dried with MgSO4 and freed from solvent. The residue, 1.1 g of brown oil, was chromatographed on 60 g of aluminium oxide (neutral, III) with methylene chloride as the eluent. There was obtained 0.67 g of crude product which was again chromato-graphed on 8 g of silica gel with methylene chloride/methanol mixtures (50:1 to 20:1). The product, 0.14 g of brown oil, was dissolved in a 10-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. After concentration to a volume of about 1 ml and addition of 3 ml of ethyl acetate there separated 0.11 g of brown crystals which were recrystallized from 4 ml of isopropanol. There were obtained 50 mg (4%) of 3-cyclopropyl-5,6,10,11-tetrahydro-8-methyl-benzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt.: 184°-187° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:21]1[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23][CH2:22]1)[C:15]1[CH:16]=[N:17][C:12]([F:11])=[CH:13][CH:14]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1ccc(F)nc1)N1CCC(F)(F)CC1
Product: O=C(NCC(c1ccc(F)nc1)N1CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(6-fluoro-3-pyridyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([I:11])[CH:3]=1.[OH-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[C:4]([I:11])[CH:3]=1
Reactant: Clc1cc(I)c2cn[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ncc2c(I)cc(Cl)cc21
Temperature: 15 °C

Procedure:
6-Chloro-4-iodo-1H-indazole (1.0 eq., 1 wt, 50 g), sodium hydroxide (2.25 eq., 0.324 wt, 16.16 g) and tetrabutylammonium hydrogensulphate (0.05 eq., 0.061 wt, 3.05 g) are stirred in THF (9.5 vols, 475 ml) at 20±3° C. under a nitrogen atmosphere for 1 hr. The mixture is cooled to 15±3° C. and benzenesulfonyl chloride (1.10 eq., 0.51 vols, 25.5 ml) was added dropwise over 20 mins maintaining the reaction temperature at <25° C. and is washed in with THF (0.5 vols, 25 ml). The resulting mixture is then stirred under a nitrogen atmosphere at 20±3° C. for at least 1 hr before checking for completion by HPLC. The reaction mixture is then added to 0.25 M hydrochloric acid solution (18 vols, 900 ml) cooled to 0±3° C. over 15 minutes maintaining the temperature of the aqueous suspension at <20° C. This is washed in with 0.25M hydrochloric acid solution (2 vols, 100 ml). The resulting orange suspension is then stirred at 2±3° C. for at least 1 hr. The solid is filtered, washed with water (2×3 vols, 2×150 ml) and sucked dry for 20 mins, then dried under high vacuum at 40° C. (±3° C.) to constant probe temperature to afford 6-chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole as an orange solid.
Reaction SMILES: [IH:1].[NH:2]1[CH2:6][CH2:5][N:4]=[C:3]1[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9]O.S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[IH:1].[Cl:15][CH2:9][C:8]([NH:7][C:3]1[NH:2][CH2:6][CH2:5][N:4]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(CO)NC1=NCCN1
Reactant: O=S(Cl)Cl
Agent: I
Solvent: ClC(Cl)Cl
Product: CC(C)(CCl)NC1=NCCN1

Procedure:
In a 1 L three necked round bottom flask, 48.26 g (0.169 mol) of 2-(4,5-dihydro-1H-imidazol-2-ylamino)-2-methyl-propan-1-ol hydroiodide was dissolved in 400 mL of chloroform. To this, 15 mL (24.46 g, 0.206 mol) of thionyl chloride was added dropwise at room temperature. The reaction was then refluxed for 36 hours after which the solvent was removed by vacuum. The product retained too much solvent after this to afford a yield calculation. NMR 3.56 (s, 4H), 3.35 (m, 2H), 1.28 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:13]([CH3:33])[C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[N:17]=[C:16]([CH3:26])[C:15]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9].O.CO.[Li+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:13]([CH3:33])[C:14]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[N:17]=[C:16]([CH3:26])[C:15]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cc(OC)ccc1N(C)c1c(-c2ccccc2)c(C)nn1-c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N(C)c2c(-c3ccccc3)c(C)nn2-c2ccccc2C)c(C(=O)O)c1
Reaction time: 24 h
Yield: 58 %

Procedure:
To a solution of the compound of step 1 (60 mg, 0.129 mmol) in a mixture of THF (4 mL), water (4 mL), and MeOH (2 mL), was added LiOH (32 mg, 1.32 mmol). The reaction mixture was vigorously stirred for 24 h, after which it was concentrated under reduced pressure, and diluted with water (10 mL). The solution was then acidified to pH ˜1 using 1 N HCl, and then extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by preparative HPLC to afford the title compound (32 mg, 58%) as a white solid. 1H NMR (400 MHz, acetone-d6) δ 2.12 (s, 3H), 2.23 (s, 3H), 2.9 (s, 3H), 3.74 (s, 3H), 6.87-6.90 (m, 2H), 6.92-6.98 (m, 1H), 7.03-7.11 (m, 1H), 7.16-7.27 (m, 4H), 7.30-7.36 (m, 2H), 7.40-7.45 (m, 2H); ES-MS m/z 428.3 (MH+); HPLC RT (min) 3.54.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][S:14]([O-:16])=[O:15].[Na+].O>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][S:14]([CH3:13])(=[O:16])=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
To a solution of 4-methanesulfonylbenzyl chloride (2 g, 10 mmol) in DMF (20 mL) at 21° C. was added sodium methanesulfinate (1.5 g, 15 mmol). After 18 h, the mixture is poured into cold water (100 mL), stirred for 30 min then filtered off to afford the title compound as a white solid.