Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@:5]1([C:13]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][O:7][C@@H:6]1[CH2:10][CH:11]=[CH2:12])(=[O:3])[CH3:2].[CH3:20][C:21]1([CH3:28])[C:25]([CH3:27])([CH3:26])[O:24][BH:23][O:22]1.O>ClCCl.[Ir+].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C@@:5]1([C:13]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][O:7][C@@H:6]1[CH2:10][CH2:11][CH2:12][B:23]1[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:28])([CH3:20])[O:22]1)(=[O:3])[CH3:2]
Reactant: C=CC[C@H]1OCC[C@@]1(NC(C)=O)C(=O)NC(C)(C)C
Reactant: CC1(C)OBOC1(C)C
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CCO[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
A solution of (2R,3S)-3-acetamido-2-allyl-N-tert-butyltetrahydrofuran-3-carboxamide (930 mg, 3.47 mmol) in dichloromethane (20 mL), was treated with chloro-1,5-cyclooctadiene iridium(I) dimer (70 mg, 3 mol %) and 1,2-bis(diphenylphosphino)-ethane (83 mg, 6 mol %). The solution was stirred at room temperature for 30 minutes and then 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.01 mL, 6.94 mmol) was added dropwise, and the reaction was stirred overnight at room temperature. The next day, the reaction mixture was poured into water and the aqueous solution was extracted using ethyl acetate (3×). The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (silica gel, 50-80% ethyl acetate in dichloromethane) gave (2R,3S)-3-acetamido-N-tert-butyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)tetrahydrofuran-3-carboxamide as a colorless oil (864 mg, 63%). 1H NMR (CDCl3, 300 MHz) δ 7.01 (s, NH, 1 H), 6.10 (s, NH, 1 H), 4.38 (m, 1 H), 4.12 (m, 1 H), 4.00 (m, 1 H), 2.96 (m, 1 H), 2.02-2.18 (m, 2 H), 1.99 (s, 3 H), 1.42-1.62 (m, 3 H), 1.36 (s, 9 H), 1.22 (s, 12 H), 0.76 (m, 2 H); MS (+CI): m/z for C20H37BN2O5: expected 396.3; found 397.4 (M+H)+.
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11](F)[N:10]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[C:11]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[N:10]=1
Reactant: Nc1nc(F)c(F)cc1F
Reactant: COc1ccc(CN)cc1
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(N)c(F)cc2F)cc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 64.4 %

Procedure:
To 10 ml of N-methylpyrrolidone were added 3.90 g of 2-amino-3,5,6-trifluoropyridine and 7.60 g of p-methoxybenzylamine, and the mixture was stirred under nitrogen atmosphere at 140° C. for one day and allowed to cool. To the solution was added 50 ml of chloroform, and the solution was washed three times with 500 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was subjected to chromatography (silica gel, 32 g; eluent: chloroform) to obtain 4.50 g of the title compound as a pale yellow crude oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][C@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[N:25])[CH:22]=2)[CH2:17][C:16]1([CH3:27])[CH3:26].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:24]([C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][C:16]([CH3:27])([CH3:26])[C@H:15]2[NH:14][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:13])=[CH:19][CH:20]=1)#[N:25]
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1N
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2cc(F)ccc2[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A mixture of 5-fluoro-1H-indole-2-carboxylic acid (56.0 mg, 0.312 mmol), (R)-3-amino-2,2-dimethyl-2,3-dihydro-1H-indene-5-carbonitrile (39.0 mg, 0.209 mmol), BOP reagent (180 mg, 0.407 mmol), N-methylmorpholine (0.13 mL, 1.18 mmol) in DMF (0.5 mL) was stirred at 50° C. for 2 hr. The desired title product (55.6 mg, 76% yield) was isolated as a white solid by prep. HPLC. LCMS (M+H)+=348.33. 1H NMR (500 MHz, DMSO-d6) δ: 11.7 (s, 1H), 8.58 (d, J=8.8 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.62 (s, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.44 (dd, J=8.8, 5.0 Hz, 1H), 7.39 (d, J=9.9 Hz, 1H), 7.28 (s, 1H), 7.04 (t, J=9.35 Hz, 1H), 5.37 (d, J=9.35 Hz, 1H), 2.87 (dd, J=22.0, 16.5 Hz, 2H), 1.21 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C@:8]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH:15]=[C:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C@H:18]([OH:26])[CH2:17]5)[C@@H:10]3[CH2:11][CH:12]=2)[CH3:9])[CH:2]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35].[Cl-].C([NH+](CC)CC)C>C(OCC)C.CN(C1C=CC=CN=1)C>[C:34]([O:26][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:8]2([CH3:9])[C@H:10]3[CH2:11][CH:12]=[C:7]2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:17]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Agent: CC[NH+](CC)CC
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Yield: 84.3 %

Procedure:
To a stirred suspension of finely powdered 17-(3-pyridyl)androsta-5,16-dien-3β-ol (3.50 g, 10 mmol) in dry diethyl ether (150 ml) coning triethylamine (2,3 ml, 16 mmol) and dimethylaminopyridine (0.012 g, 0.1 mmol) was added acetyl chloride (1.0 ml, 14 mmol). The mixture was then stirred at ambient temperature for 12 h, over which time a thick whim precipitate of triethylammonium chloride had formed. The mixture was then filtered and the filtrate concentrated to afford the crude product which was recrystallised firstly from ethanol/water (1:1), then finally from hexane to afford the title compound (3.30 g, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Br[CH2:19][CH2:20][CH2:21][CH2:22]Br.C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1>O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCCCCBr
Reactant: Nc1ccc(Br)c(OCCN2CCCCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(N2CCCC2)cc1OCCN1CCCCC1
Temperature: 110 °C

Procedure:
4-Bromo-3-(2-{piperidin-1-yl}ethoxy)aniline (2.99 g), 1,4-dibromobutane (1.2 ml), diisopropylethylamine (4.18 ml) and toluene (15 ml) were stirred and heated at 110° C. for 18 h. When cool, water (20 ml) was added, and the mixture was extracted with ethyl acetate (2×30 ml). The combined organic phase was washed with water, brine, dried (MgSO4) and evaporated to give the product as an orange-brown oil (2.25 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([S:13]([CH2:16][CH2:17][SH:18])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:20]1[C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:26]=2)[N:21]=1>CC(C)=O>[C:7]1([S:13]([CH2:16][CH2:17][S:18][C:20]2[C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:33]([F:34])([F:36])[F:35])[CH:26]=3)[N:21]=2)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2nc1Cl
Reactant: O=S(=O)(CCS)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1cc2cc(C(F)(F)F)ccc2nc1SCCS(=O)(=O)c1ccccc1
Temperature: 70 °C
Yield: 70 %

Procedure:
206 mg (1.5 mmol) K2CO3 and 303 mg (1.5 mmol) 2-(phenylsulfonyl)ethanethiol were added to a solution of 827 mg (1.0 mmol) 2-chloro-6-(trifluoromethyl)quinoline-3-carboxylic acid (precursor VVV03) in acetone (3 ml) and the mixture was heated for 5 h at 70° C. Then it was filtered and the filtrate was concentrated to small volume under vacuum. The residue was dissolved in water and acidified with a 1N hydrochloric acid. It was then extracted with EE and the organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. Crystallisation (DCM/hexane) of the residue yielded 316 mg (0.7 mmol, 72%) 2-(2-(phenylsulfonyl)ethylthio)-6-(trifluoromethyl)quinoline-3-carboxylic acid.
Reaction SMILES: C(O)(=[O:3])C.[BH4-].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[CH2:27])[CH:24]=3)[N:19]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:18]=2[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][CH2:27][OH:3])[CH:24]=3)[N:19]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:18]=2[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:15][CH:16]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(=O)O
Reactant: C=Cc1ccc2c(c1)c(-c1ccc(C(C)(C)C)cc1)c(C(=O)OCC)n2Cc1cccc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(CCO)ccc2n1Cc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Acetic acid (63 μL, 66 mg, 1.1 mmol) was added slowly to a cooled (0° C.) and stirred slurry of sodium borohydride (41.6 mg, 1.10 mmol) in tetrahydrofuran (2 mL). The mixture was stirred for 1 h and then a solution of ethyl 3-(4-tert-butylphenyl)-1-(3-methoxybenzyl)-5-vinyl-1H-indole-2-carboxylate (Example 129, 430 mg, 0.920 mmol) in tetrahydrofuran (5+2 mL rinse) was added. The reaction was stirred overnight and then cooled (0° C.). The reaction was quenched by successive addition of EtOH (6 mL), 6 M aqueous sodium acetate (5 mL) and 27% aqueous hydrogen peroxide (5 mL). The mixture was heated (50° C.) for 1 h and then cooled. The reaction was diluted with water (100 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 30% ethyl acetate/hexane afforded 325 mg (75%) of desired product. The product had: 1H NMR (300 MHz, CDCl3) δ 7.28-7.48 (m, 6 H), 7.15-7.22 (m, 2 H), 6.75 (dd, 1 H), 6.64-6.72 (m, 2 H), 7.76(s, 2 H), 4.08 (q, 2 H), 3.78-4.00 (m, 3 H), 3.73 (s, 3 H), 2.91 (t, 2 H), 1.39 (s, 9 H), 0.95 (t, 3 H).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18](N)=[O:19])[CH:15]=[CH:16][C:3]1=2.[OH-].[K+].O.C([OH:27])C>C(O)(=O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:21])[C:18]([OH:27])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CCO
Reactant: CC(C(N)=O)c1ccc2c(c1)Oc1ncccc1CC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)Oc1ncccc1CC2=O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
The mixture of 40 mg of 2-(5,6-dihydro-6-oxo benzo[b]-pyrido[3,2-f]oxepin-9-yl)-propionamide, 180 mg of potassium hydroxide, 1.5 ml of water and 5 ml of ethanol was refluxed with stirring for 5 hours. After cooling, the solvent was distilled off to obtain the residue, to this was added ice-water and the mixture was acidified with acetic acid and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the oil, which was chromatographed over silica gel, eluted with chloroform-ethanol, and there was obtained 20 mg of 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]oxepin-9-yl)-propionic acid as pale yellow powder.
Reaction SMILES: [C:1]1(=O)[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3](=[O:9])O1.[Cl-].[Cl-].[Cl-].[Al+3].O.O.[NH2:17][NH2:18].[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(=S)=S.CCO>[C:19]1([C:1]2[C:5]3[CH2:6][CH2:7][CH2:8][C:4]=3[C:3](=[O:9])[NH:17][N:18]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccccc1
Reactant: NN
Reactant: O=C1OC(=O)C2=C1CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: S=C=S
Product: O=c1[nH]nc(-c2ccccc2)c2c1CCC2

Procedure:
5,6-dihydro-1H-cyclopenta[c]furan-1,3(4H)-dione (1 g, 7 mmol) was added slowly to a well-stirred suspension of aluminum trichloride (1.9 g, 14 mmol) in 15 mL of benzene and 15 mL of CS2. The red reaction mixture was refluxed for 1.5 hours. After cooling, the mixture was poured into water, and extracted with CHCl3. The organic layer was dried (Na2SO4), filtered and concentrated to afford a solid. The solid was dissolved in 20 mL of EtOH, and 5 mL of hydrazine hydrate was added. The mixture was refluxed for 12 hours, allowed to cool, and filtered. The solid collected was washed with water, and dried to afford the title compound. MS (APCI+) M/Z 213 (M+H)+.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][O:32][CH2:33][CH2:34][NH:35][CH3:36]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:35]([CH2:34][CH2:33][O:32][CH3:31])[CH3:36])=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CNCCOC
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: COCCN(C)C(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 20.9 mg (0.23 mmol) of N-(2-methoxyethyl)-N-methylamine are reacted together by general method E. 20.4 mg (31.3% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][S:11]([C:14]2[S:18][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C=O.[CH3:25][NH:26][CH3:27].CO.[CH:30](Cl)(Cl)Cl>C(O)C>[CH3:25][N:26]([CH2:30][C:7]1[CH:6]=[C:5]([CH2:8][CH2:9][CH2:10][S:11]([C:14]2[S:18][C:17]([S:19]([NH2:22])(=[O:20])=[O:21])=[CH:16][CH:15]=2)(=[O:12])=[O:13])[CH:4]=[CH:3][C:2]=1[OH:1])[CH3:27]
Reactant: ClC(Cl)Cl
Reactant: CNC
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)CCCc2ccc(O)cc2)s1
Agent: C=O
Solvent: CCO
Solvent: CO
Product: CN(C)Cc1cc(CCCS(=O)(=O)c2ccc(S(N)(=O)=O)s2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of product from Step C, (1.2 g, 3.3 mmol) in ethanol (16.5 ml) was added formaldehyde (0.3 ml, 37% in water, 3.6 mmol) and dimethylamine (0.8 ml, 40% in water, 6.6 mmol). The reaction was refluxed for 3 hours and then stirred at room temperature overnight. The solution was concentrated, 3N HCl added and extracted with ethyl acetate. The aqueous phase was made basic with saturated bicarbonate solution and extracted with ethyl acetate. Drying and solvent evaporation gave and oil (1.1 g). Column chromatography (silica gel, 5% methanol-CHCl3) gave the title compound (0.8 g, 57%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]1[CH2:17][O:16][S:13](=[O:15])(=[O:14])[CH2:12][CH2:11]1.CC(C)=O>O1CCCC1.CCO>[CH2:1]([NH:9][CH2:17][CH2:10][CH2:11][CH2:12][S:13]([OH:16])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: O=S1(=O)CCCCO1
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(C)=O
Product: CCCCCCCCNCCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31 %

Procedure:
To a solution of octylamine (2.20 g, 17.0 mmol) in tetrahydrofuran (11 mL) was added 1,4-butane sultone (2.30 g, 16.2 mmol). The solution was heated to reflux for 5 hours. The reaction was cooled to room temperature. The product formed a gel. A few drops of EtOH were added to dissolve the product. The solution was poured in a large excess of acetone (25 mL). After 5 minutes, a white solid precipitated. The solid was collected by filtration and dried in vacuo. The product was dissolved in EtOH and Dowex 50×8 resin (pre-washed, 6 g) was added to the solution. The suspension was stirred for 15 minutes and the resin was filtered. The filtrate was evaporated under educed pressure and the product was dried in vacuo. Yield: 31%. 1H NMR (DMSO, 500 MHz) δ ppm 8.24 (s (broad), 1H), 2.85 (m, 4H), 2.45 (m, 2H), 1.64 (m, 4H), 1.61 (m, 2H), 1.25 (m, 10H), (m, 2H), 0.85 (t, 3H, J=6.8 Hz). 13C (DMSO, 125 MHz) δ ppm 51.22, 47.54, 47.38, 31.82, 29.14, 26.59, 26.13, 25.51, 22.95, 22.75, 14.64. ES-MS 266 (M+1).
Reaction SMILES: C(Cl)Cl.[CH2:4]([N:6]([CH2:9]C)[CH2:7][CH3:8])C.CN(C)C([C@@H:15]1[CH2:20][C@@H:19]([NH:21][S:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:24])=[O:23])[C@H:18](O)[CH2:17]C1)=O.CS(Cl)(=O)=[O:37]>O>[CH3:9][N:6]([CH3:4])[C:7]([C@@H:8]1[CH2:15][C@H:20]2[N:25]([C:26]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:32])[S:22](=[O:24])(=[O:23])[NH:21][C@H:19]2[CH2:18][CH2:17]1)=[O:37]
Reactant: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](NS(=O)(=O)NC(=O)OC(C)(C)C)C1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)[C@H]1CC[C@@H]2NS(=O)(=O)N(C(=O)OC(C)(C)C)[C@@H]2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Methylene chloride (200 ml) and triethylamine (18.5 ml) were added to tert-butyl {[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]sulfamoyl}carbamate (20 g), and the obtained solution was then cooled to approximately 0° C. Methanesulfonyl chloride (5.2 ml) was added dropwise to the reaction solution, and the obtained mixture was then stirred for approximately 1 hour. Thereafter, water (100 ml) was added to the reaction mixture, and the organic layer was then separated. The solvent was distilled off from the organic layer under reduced pressure. To the residue, acetonitrile (200 ml) and triethylamine (15.4 ml) were added, and the obtained mixture was then heated to approximately 90° C., followed by stirring the mixture for approximately 2 hours. Thereafter, the reaction mixture was cooled to room temperature, 10% saline (100 ml) was then added to the mixture, and the organic layer was then separated. The aqueous layer was extracted with ethyl acetate (100 ml) again. The gathered organic layers were concentrated, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (14.02 g, yield: 74%) in the form of powder.
Reaction SMILES: C[C:2]([C:5]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])(C)[C:6]([O-:8])=[O:7])(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][C:11]1[C:12]2[CH2:16][O:15][C:14](=[O:17])[C:13]=2[CH:18]=[CH:19][C:10]=1[CH:5]([CH3:2])[C:6]([OH:8])=[O:7]
Reactant: Cc1c(C(C)(C(=O)[O-])C(C)(C)C)ccc2c1COC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(C)C(=O)O)ccc2c1COC2=O
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanoate (400 mg, 1.4 mmol) in 10 mL of anhydrous DCM was added TFA (2.5 mL) dropwise at r.t. Then the mixture was stirred for 1 hour. The solvent was removed under vacuum to give the crude 2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanoic acid, which was used for next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[N:4]([CH2:10][CH2:11][CH3:12])[C:5](=[O:9])[NH:6][C:7]=1[NH2:8].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=1.CCN=C=NCCCN(C)C.Cl>CO>[NH2:8][C:7]1[NH:6][C:5](=[O:9])[N:4]([CH2:10][CH2:11][CH3:12])[C:3](=[O:13])[C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([Cl:14])=[N:16][CH:17]=1
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: CCCn1c(=O)[nH]c(N)c(NC(=O)c2ccc(Cl)nc2)c1=O
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A mixture of 5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione (2.0 g, 11.0 mmol), 6-Chloro nicotinic acid (1.86 g, 11.8 mmol) in methanol (40 ml) were cooled to 0° C. and added EDCI.HCl (4.2 g, 22 mmol). The reaction mixture was stirred at 25° C. for 20 hours and the solvents were removed under reduced pressure. To this residue water (20 ml) was added and the precipitate was filtered off, and washed sequentially with cold water (20 ml) and methanol (5 ml) to obtain N-(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-6-chloro-nicotinamide as an off white solid. (2.47 g, 70%).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]([CH3:17])C=CN=2)=[CH:6][CH:5]=1.[CH:19]([O-])=O.[NH4+:22]>C(O)(C)C.[Pd]>[NH:22]1[CH:19]=[C:12]([CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:18])=[CH:9][CH:8]=2)[N:13]=[CH:17]1
Reactant: COC(=O)c1ccc(/C=C/c2nccn2C)cc1
Reactant: O=C[O-]
Reactant: [NH4+]
Agent: [Pd]
Solvent: CC(C)O
Product: O=C(O)c1ccc(CCc2c[nH]cn2)cc1
Temperature: 150 °C

Procedure:
E-4-[2-(1-Methyl-1H-imidazol-2-yl)-vinyl]-benzoic acid methyl ester was hydrogenated using Pd/C (10% of substrate weight), ammonium formate (5 equivalents) in isopropanol heated by microwave irradiation (200 W) for 5 mins at 150° C. The solution was filtered through celite to remove the insoluble catalyst, diluted with water and freeze-dried to remove the excess of ammonium formate. The obtained solid was hydrolysed by 6N aqueous HCl solution heated by microwave irradiation (200 W) for 3 mins at 150° C. The solution was freeze dried to give to the hydrochloride salt of the title compound as a white powder m/z=217 in MS ES+, which was characterised by HPLC and MS.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH:28]([C:36](O)=[O:37])[CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:36]([CH:28]5[CH2:29][C:30]6[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=6)[O:26][CH2:27]5)=[O:37])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1COc2ccccc2C1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1COc2ccccc2C1

Procedure:
The title compound, white solid (28.5 mg, 71%), MS (ISP) m/z=491.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and chroman-3-carboxylic acid.