Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.O.[NH2:15][NH2:16]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:15][NH2:16])=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NN
Reactant: Clc1cc(N2CCCC2)c(Cl)nn1
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(N2CCCC2)c(Cl)nn1

Procedure:
3,6-Dichloro-4-(pyrrolidin-1-yl)pyridazine (7.2 g, 33 mmol) and hydrazine hydrate (9.96 g, 0.2 mol) were heated at reflux in dioxan (130 ml) for 6 hours. Upon cooling the desired isomer crystallized from the reaction and was collected by filtration (4.1 g, 58%). 1H NMR (250 MHz, d6-DMSO) 1.79-1.84 (4H, m), 3.25-3.40 (4H, m), 4.12 (2H, br), 6.09 (1H, s), 7.47 (1H, s). MS (ES+) 214 [MH]+, 216 [MH]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[Cl:28][CH2:29][C:30](O)=O>>[Cl:28][CH2:29][CH2:30][N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][C@H:21]1[CH:23]([CH3:25])[CH3:24]
Reactant: O=C(O)CCl
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C(C)C)CO3
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N(CCCl)[C@H](C(C)C)CO3
Yield: 52.8 %

Procedure:
Compound 152 was prepared according to General Method 5 (EXAMPLE 2) from (3R)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (16 mg, 0.05 mmol) and NaBH4 pellets (>10 equiv) in 0.5 g chloroacetic acid to afford 11 mg (58%) of (3R)-4-(2-chloroethyl)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (11 mg, 0.03 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 4 mL of 1:1 acetic acid:concentrated HCl (0.02M) heated at 90° C. for 4 h to afford Compound 152. 1H NMR (500 MHz, CDCl3) 12.06 (bs, 1H), 7.13 (s, 1H), 7.12 (d, J=8.8, 1H), 6.98 (d, J=8.8, 1H), 4.53 (dd, J=10.7, 1.5, 1H), 3.88 (dd, J=10.7, 2.4, 1H), 3.82 (m, 1H), 3.71 (m, 1H), 3.63 (m, 1H), 3.49 (m, 1H), 2.93 (m, 1H), 1.82 (m, 1H), 0.99 (d, J=10.3, 3H), 0.98 (d, J=10.3, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].N1CCCCC1.[Br-:13].[NH2:14][C:15]1[CH:40]=[CH:39][CH:38]=[CH:37][C:16]=1[CH2:17][P+:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCl>[Br-:13].[Cl:1][CH2:2][CH2:3][C:4]([NH:14][C:15]1[CH:40]=[CH:39][CH:38]=[CH:37][C:16]=1[CH2:17][P+:18]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:5]
Reactant: Nc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C(CCCl)Nc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 48 %

Procedure:
3-Chioropropionyl chloride (3.0 ml, 32 mmol) and piperidine (3.5 ml, 43.5 mmol) were added to a suspension of 2-aminobenzyltriphenylphosphonium bromide (13.0 g, 29 mmol) (synthesised using the procedure of Capuano et al, Chem. Ber., 1986, 119, 2069-2074) in dichloromethane (60 ml) under a nitrogen atmosphere. The mixture was heated at reflux for 30 min. and then cooled to room temperature. Dichloromethane (60 ml) and hydrochloric acid (1N, 50 ml) were added and the precipitated solid was collected by filtration, washed with dichloromethane and dried in vacuo to give 2-(3-chloropropionylamino)benzyltriphenylphosphonium bromide (7.5 g, 48%). The filtrate was diluted with dichloromethane (300 ml) and washed with sodium carbonate (satd., 150 ml). Evaporation of the dichloromethane gave a residue which was triturated with ether (200 ml) and the white solid collected to afford a second crop of product (5.0 g, 32%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCOC(C)=O.O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=2[NH2:8])[CH2:15][CH2:14]1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN(c2cncc([N+](=O)[O-])c2N)CC1
Yield: 56.9 %

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (LXIX) (618 mg, 2.83 mmol) in 1-methylpiperazine (1 mL, 8.51 mmol) was heated at 140° C. overnight. The reaction was poured into an EtOAc/H2O mixture; the organic layer was separated, dried over MgSO4 and concentrated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH(7N NH3):CHCl3) to give 3-(4-methylpiperazin-1-yl)-5-nitropyridin-4-amine (CXVII) as a yellow solid (382 mg, 1.61 mmol, 56.7% yield). 1H NMR (CDCl3, 500 MHz) δ ppm 2.20 (s, 3H), 2.35-2.37 (m, 4H), 4.52-3.54 (m, 4H), 5.96 (s, 1H), 7.42 (s, 2H), 8.78 (s, 1H); ESIMS found C10H15N5O2 m/z 238 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)(OC)=[O:2].[BH4-].[Li+].Cl>C1COCC1.CO>[OH:2][CH2:1][C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][CH2:18][NH:19][S:20]([C:23]([F:25])([F:24])[F:26])(=[O:21])=[O:22])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1
Reactant: COC(=O)c1cnc2cccc(CN(CCCNS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C)n12
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCNS(=O)(=O)C(F)(F)F)Cc1cccc2ncc(CO)n12
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 396 mg (0.80 mmol) of 3-carbomethoxy-5-[N-tert-butoxycarbonyl-N-(3-trifluoromethane-sulfonamidopropan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in a mixture of 5.0 ml of THF and 1.0 ml of methanol was added, at room temperature, 87.12 mg (4.00 mmol) of lithium borohydride with small portions. The mixture was heated for 30 minutes under reflux. The reaction mixture was cooled to room temperature, and poured into ice-water. The mixture was neutralized with 1N HCl, and extracted with 50 ml of chloroform. The organic layer was washed with 50 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=20:1) to afford 269 mg of the desired compound (72%, a pale yellow liquid).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3([CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[O:13][C:12]3[C:21]([CH3:28])=[C:22]([CH3:27])[C:23]([NH2:26])=[C:24]([CH3:25])[C:11]2=3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.CO.C(OC(C)C)(C)C>>[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:26][C:23]2[C:22]([CH3:27])=[C:21]([CH3:28])[C:12]3[O:13][C:14]4([CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[CH:10]([C:7]4[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=4)[C:11]=3[C:24]=2[CH3:25])=[O:35])=[CH:32][CH:31]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CO
Solvent: CC(C)OC(C)C
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Yield: 38 %

Procedure:
By using 3-(4-isopropylphenyl)-1′,4,6,7-tetramethylspiro[benzofuran-2(3H),4′-piperidine]-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 38%. Melting point: 271-272° C. (Methanol-isopropyl ether)
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13])C.Cl.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][NH2:40])=[CH:35][CH:34]=1)#[N:32].O>CN(C)C=O>[CH3:25][N:9]1[C:8](=[O:26])[C:7]([C:6]2[N:39]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[N:40]=[CH:4][CH:5]=2)=[C:12]([CH3:13])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:10]1=[O:24]
Reactant: N#Cc1ccc(NN)cc1
Reactant: CCOC(C#Cc1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1=O)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 5-(3,3-diethoxyprop-1-ynyl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)-pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 61) and 4-cyanophenylhydrazine hydrochloride (27.9 mg) in N,N-dimethy formamide (2.0 ml) was stirred at 130° C. for seven hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with water (10 ml×2) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (17.9 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:43])([CH3:42])[CH2:6][N:7]([S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32])[CH2:8][C@@H:9]([OH:30])[C@@H:10]([NH:18][C:19](=[O:29])[O:20][C@@H:21]1[C@H:28]2[C@H:24]([O:25][CH2:26][CH2:27]2)[O:23][CH2:22]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.[CH3:53][N:54]([CH3:58])[C:55](Cl)=[O:56]>C1COCC1>[CH2:11]([C@H:10]([NH:18][C:19](=[O:29])[O:20][C@@H:21]1[C@H:28]2[C@H:24]([O:25][CH2:26][CH2:27]2)[O:23][CH2:22]1)[C@H:9]([OH:30])[CH2:8][N:7]([CH2:6][C:5]([CH3:43])([CH3:42])[CH2:4][CH2:3][CH2:2][NH:1][C:55]([N:54]([CH3:58])[CH3:53])=[O:56])[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCN)c1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCNC(=O)N(C)C)c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A solution of 50 mg (0.081 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-3-((5-amino-2,2-dimethylpentyl) [3-(methylamino)phenyl]sulfonylamino)-1-benzyl-2-hydroxypropyl]carbamate and 17 μL (0.097 mmol) of N,N-diisopropylethylamine in 5 mL of anhydrous THF at 0° C. was treated with 8.2 μL (0.089 mmol) of N,N-dimethylcarbamyl chloride. The solution was allowed to warm to RT with stirring. After 18 hours the solution was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 44 mg (79%) of the desired compound as a white foam. H1-NMR (CDCl3): 7.31-7.11 (m, 6H), 7.03 (d, 1H), 6.95 (s, 1H), 6.73 (d, 1H), 5.92 (d, 1H), 5.60 (d, 1H), 4.94 (q, 1H), 4.63 (t, 1H), 4.19 (m, 2H), 3.94-3.73 (m, 4H), 3.63 (m, 2H), 3.30-3.00 (m, 6H), 2.91-2.78 (m, 11H), 2.69 (dd, 1H), 1.59-1.19 (m, 6H), 0.94 (s, 3H), 0.86 (s, 3H). MS(ESI): 690(M+H).
Reaction SMILES: [CH3:1][C:2]([CH2:6][OH:7])([CH2:4][OH:5])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH3:39])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]2[O:7][CH2:6][C:2]([CH3:3])([CH3:1])[CH2:4][O:5]2)=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH3:39])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCOc1cc(C=O)ccc1OCc1ccccc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOc1cc(C2OCC(C)(C)CO2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
1.45 g (13.9 mmol) of neopentylglycol and 88 mg (0.46 mmol) of p-toluenesulfonic acid monohydrate were added to a solution of 1.25 g (4.63 mmol) of 4-benzyloxy-3-propoxybenzaldehyde in 50 ml of toluene and then refluxed for 1 hour under a water separator. Thereafter, the reaction mixture was cooled to room temperature and partitioned between toluene and a saturated sodium bicarbonate solution, and the organic phase was washed several times with water, dried over magnesium sulfate, filtered and evaporated down. Crystallization of the residue from 10 ml of diethyl ether gave 1.07 g of 2-(4-benzyloxy-3-propoxyphenyl)-5,5-dimethyl-1,3-dioxane.
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.[CH2:26]([SH:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[CH2:26]([S:38][C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCS
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCSc1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc2c1
Temperature: 150 °C

Procedure:
To a 3-liter three-necked flask equipped with stirrer, thermometer, nitrogen inlet and distillation set-up are charged 357.8 g (1 mole) of 5-chloro-(2-hydroxy-3,5-di-tert-butyl-phenyl)-2H-benzotriazole, available from CIBA-GEIGY Corp. as TINUVIN® 327, 216.8 g (1.05 mole) of n-dodecyl mercaptan and 600 mL of N,N-dimethylformamide (DMF). Then 73.9 g (0.54 moles) of potassium carbonate and 2 g of potassium iodide are added and the mixture heated for 20 hours at 150° C. under a nitrogen atmosphere. Any water which is liberated as a result of the reaction distills off as an azeotrope until the head-temperature reaches 132° C. After 20 hours at 150° C. the starting 2H-benzotriazole is totally consumed. With partial vacuum at 80°-100° C., most of the DMF is distilled off. To the resulting oil is added at 80° C. 1 L of toluene and 500 mL of water. The aqueous phase is drained off. The toluene solution is washed twice more with 500 mL water containing 1 mL of acetic acid. The organic solution is freed from residual water by azeotropic distillation until a clear solution is obtained. Under partial vacuum all but about 100 mL of toluene is distilled off at 70° C. The residue is diluted at 60° C. with 2 L of isopropanol and some product seeds are added The product gradually crystallizes and the mixture is slowly cooled to 10° C. The product is filtered off and washed with 300 mL of isopropanol to yield 490.4 g (93.6% of theory) of the title compound, mp. 62°-64° C.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:25][OH:26])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].[F:31][CH:32]([F:43])[O:33][C:34]1[CH:41]=[C:40](F)[CH:39]=[CH:38][C:35]=1[C:36]#[N:37].O>CN(C)C=O>[F:31][CH:32]([F:43])[O:33][C:34]1[CH:41]=[C:40]([O:26][CH2:25][C:11]2[S:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:4][CH:5]=3)=[N:13][C:12]=2[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:22])([F:24])[F:23])[CH2:17][CH2:16]2)[CH:39]=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Reactant: N#Cc1ccc(F)cc1OC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1OC(F)F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of 3 g of [2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-methanol in 12 mL of dimethylformamide at 5° C. was added 319 mg of a 55% suspension of sodium hydride in mineral oil. The resulting mixture was stirred for 30 minutes at 5° C. 4.7 mL of the resulting solution was slowly added to a solution 319 mg of 2-difluoromethoxy-4-fluoro-benzonitrile in 1.2 mL of dimethylformamide at 5° C. The resulting mixture was stirred at 5° C. allowing the temperature to warm up to room temperature. It was then heated in a sealed tube to 60° C. under microwave irradiation for 15 minutes. After allowing it to cool down to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 50/ethyl acetate 50) to give 0.83 g of 2-difluoromethoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzonitrile.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:23][C@@H:22]3[CH3:33])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:34]([O:36]C)=[O:35])[CH:17]=3)[N:12]=1)=[CH:6][CH:5]=2.[OH-].[Na+].O>CO>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:23][C@@H:22]3[CH3:33])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:34]([OH:36])=[O:35])[CH:17]=3)[N:12]=1)=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2cc(-c3nc4ccc(C(=O)O)cc4nc3N3CCN(c4ccccn4)C[C@@H]3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of (S)-methyl 2-(2-methyl-1H-indol-5-yl)-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.30 mmol) in methanol (20 ml) was added sodium hydroxide (36 mg, 0.90 mmol) and water (1 ml) The resulting solution was stirred overnight at room temperature and the mixture was concentrated under vacuum dissolved in water (30 ml), adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford (S)-2-(2-methyl-1H-indol-5-yl)-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (44 mg, 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>O1CCCC1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:33])[CH:31]=[CH2:32])[CH:7]=[CH:6][CH:5]=3)[C:16]=12
Reactant: CC(C)n1nc(-c2cccc(N)c2)c2c(N)ncnc21
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Reaction time: 1 h
Yield: 26 %

Procedure:
A solution of tetrahydrofuran (20 mL), compound 22 (219 mg, 0.817 mmol) and diisoproylethylamine (156 μL, 0.895 mmol) was cooled to 0° C. Acryloyl chloride (67 μL, 0.828 mmol) was added and the reaction was allowed to proceed for 1 hour and afterwards concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL) and washed with saturated sodium bicarbonate (20 mL). The aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The product was purified by preparative RP-HPLC and lyophilized (70 mg, 26% yield): 1H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.73 (d, J=8.0, 1H), 7.52 (t, J=7.9, 1H), 7.39 (d, J=7.7, 1H), 6.47 (dd, J=17.0, 10.1, 1H), 6.29 (dd, J=17.0, 2.0, 1H), 5.80 (dd, J=10.1, 2.0, 1H), 5.11 (hept, J=6.6, 1H), 1.51 (d, J=6.7, 6H); 13C NMR (100 MHz, DMSO) δ 163.47, 154.87, 151.90, 150.94, 144.73, 139.53, 132.54, 131.68, 129.88, 127.31, 123.42, 119.96, 119.22, 96.91, 48.80, 21.74; [M+H]+ calculated for C17H18N6O 323.1, found 323.5.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]([OH:25])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[CH:5]([CH2:4][N:3]([CH3:2])[C:23](=[O:25])[CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8]2
Reactant: O=C(O)Cc1cccs1
Reactant: CNCC1CCCc2cc(OC)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCCC2CN(C)C(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
The product from Example 3 was converted to the free base (6 g) and dissolved in dry tetrahydrofuran (THF) (125 ml). Then 2-thiopheneacetic acid (3.62 g) and 1-hydroxybenzotriazole (5.1 g) was added followed by the dropwise addition of N,N'-dicyclohexylcarbodiimide (DCC) 6.7 g in dry THF (50 ml). The reaction was stirred at room temperature overnight, then filtered and evaporated to dryness. The oil was dissolved in EtOAc and upon standing precipitation occurred. This was filtered, and the filtrate washed with 1 N NaOH, then 1 N HCl and brine. The organic phase was dried (MgSO4), filtered and concentrated to afford the product, 7.4 g, 91% yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:14]=2[O:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:20][C:18]1[CH:17]=[CH:16][C:15]2[O:11][CH2:12][O:13][C:14]=2[CH:19]=1)([O-:10])=[O:9]
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1ccc2c(c1)OCO2
Yield: 64.5 %

Procedure:
9.3 g (66 mmol) of 2-fluoro-nitrobenzene and 10 g (73 mmol) of benzo[d][1,3]dioxol-5-ylamine were dissolved in N,N-dimethylformamide (60 mL) and 10.9 g (79 mmol) of potassium carbonate was added thereto. Mixed solution was heated to reflux for 10 hours while stirring. The reaction mixture was poured into water, and extracted with ethyl acetate. The extracted organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (developing solvent: ethyl acetate:hexane=1:3), to obtain 11 g (yield: 65%) of N-(2-nitrophenyl)benzo[d][1,3]dioxol-5-ylamine as red-purple crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH2:10]([O:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([N:18]=[C:19]=[O:20])=[O:17])[CH:11]=[CH2:12].C([O-])(=O)/C=C/C([O-])=O>>[CH2:10]([O:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([NH:18][C:19]([NH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1)=[O:20])=[O:17])[CH:11]=[CH2:12]
Reactant: C=CCOc1ccccc1C(=O)N=C=O
Reactant: NC1CN2CCC1CC2
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: C=CCOc1ccccc1C(=O)NC(=O)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine (0.28 g, 2.2 mmol) and 2-allyloxybenzoyl isocyanate (0.53 g, ca 2.2 mmol). The product (0.61 g) was converted to the 1:1 fumarate.
Reaction SMILES: ClS(C1C=C(C=CC=1F)C(O)=O)(=O)=O.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1.[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[C:28]([S:32](NCC)(=[O:34])=[O:33])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[Cl:21][C:22]1[CH:30]=[C:29]([F:31])[C:28]([S:32]([NH:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:34])=[O:33])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: CCNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Reactant: NC1CCCC1
Agent: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Product: O=C(O)c1cc(S(=O)(=O)NC2CCCC2)c(F)cc1Cl

Procedure:
1.01 g (3.7 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid was added to 1.08 mL (10.9 mmol) cyclopentylamine following the general procedure in for 2-chloro-5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid. Crude product was used in subsequent step without further purification