Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[CH2:14][NH:13][CH2:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O.[BH4-].[Na+].[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[C:3]2[CH2:4][CH:5]3[CH2:14][NH:13][CH2:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Brc1cccc2c1cc1n2CCNC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Brc1cccc2c1CC1CNCCN21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.2 %

Procedure:
9-Bromo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole (3.5 g, 13.9 mmol) was dissolved in THF (15 mL) and trifluoroacetic acid (30 mL) and cooled to 0° C. Sodium borohydride (1 g, 27.9 mmol) was added in portions, the mixture was stirred for 90 min at room temperature and added to an ice/water mixture (150 mL). After addition of sodium hydroxide solution (28%, 35 mL) to render the mixture basic it was extracted with dichloromethane. Organic phases were pooled, washed with brine, dried with MgSO4 and the solvent was evaporated. Chromatography on silica gel (dichloromethane/methanol/ammonia 180:10:1) yielded 9-bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (2.4 g, 68%) as a yellowish solid, MS: m/e=252.0 (M+).
Reaction SMILES: [F:1][CH:2]1[CH:7]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=3[NH:10][C:9]2=[O:21])[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([C:29]([C:31]2[CH:41]=[C:40]([CH3:42])[C:34]3[N:35]([CH3:39])[C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:24]=1.CO>CN(C=O)C>[CH3:39][N:35]1[C:34]2[C:40]([CH3:42])=[CH:41][C:31]([C:29]([C:25]3[N:26]=[CH:27][N:28]=[C:23]([N:4]4[CH2:5][CH2:6][CH:7]([N:8]5[CH2:14][CH2:13][C:12]6[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=6[NH:10][C:9]5=[O:21])[CH:2]([F:1])[CH2:3]4)[CH:24]=3)=[O:30])=[CH:32][C:33]=2[O:37][C:36]1=[O:38]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1F)C(=O)N2
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1F)C(=O)N2

Procedure:
60 mg (0.21 mmol) 3-(3-fluoro-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one, 60 mg (0.20 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.040 mL (0.30 mmol) TEA were stirred overnight in 1 mL DMF at RT. The reaction mixture was combined with 2 mL MeOH and the precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([N:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][O:27][C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:37]=4[N:36]=[C:35]([CH3:38])[CH:34]=[CH:33]5)[C:20]=3[Cl:39])[CH3:18])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:51](Cl)(=[O:53])[CH3:52]>C(#N)C>[C:51]([NH:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([N:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][O:27][C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:37]=4[N:36]=[C:35]([CH3:38])[CH:34]=[CH:33]5)[C:20]=3[Cl:39])[CH3:18])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:53])[CH3:52]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)Cc4ccc(C(=O)c5ccc(N)cc5)n4C)c3Cl)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)Nc1ccc(C(=O)c2ccc(CC(=O)N(C)c3ccc(Cl)c(COc4cccc5ccc(C)nc45)c3Cl)n2C)cc1
Reaction time: 2 h
Yield: 50 %

Procedure:
Compound 56 (0.033 g, 0.056 mmol) was dissolved in 5 mL acetonitrile. To this was added diisopropylethylamine (0.032 mL, 0.184 mmol) and acetyl chloride (0.05 mL, 0.703 mmol). The reaction was allowed to stir for 2 hours then was quenched with the addition of ˜2 ml of methanol. The solvents were evaporated and the residue purified via reverse phase chromatography eluting with a gradient of acetonitrile:water 10-90%.The proper fractions were isolated and the solvents were lyophilized to yield the product (0.021 g, 0.028 mmol) as an off-white powder. 1H NMR (CDCl3): δ 8.61 (d, 1H), 7.84-7.47 (m, 9H), 7.37 (d, 1H), 6.55 (d, 1H), 5.86 (d, 1H), 5.60 (s, 2H), 3.84 (s, 3H), 3.53 (m, 2H), 3.28 (s, 3H), 2.93 (s, 3H), 2.21 (s, 3H); MS: M+1=629.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH2:18][CH3:19])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:9]([C:8]3[C:7]([CH2:18][CH3:19])=[CH:6][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[C:13]([CH:12]=3)[C:14]([O:16][CH3:17])=[O:15])=[O:10])[CH2:22][CH2:23]2)=[CH:28][CH:29]=1)#[N:32]
Reactant: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)O
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a round-bottom flask were added a solution of 4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 215.4, 1.15 g, 4.38 mmol, 1.00 equiv), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.07 g, 4.80 mmol, 1.10 equiv), HBTU (2.50 g, 6.59 mmol, 1.50 equiv), and DIEA (1.07 g, 8.28 mmol, 3.00 equiv) in N,N-dimethylformamide (10 mL). The resulting solution was stirred for 1 h at 25° C. The reaction was then quenched by the addition of 20 mL of water. The resulting mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:3) to yield 1.80 g (95%) of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O.NN>CO.[Fe](Cl)(Cl)Cl>[CH3:20][N:2]([CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([NH2:15])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CC2
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1N)N(C(=O)CN(C)C)CC2
Temperature: 60 °C
Yield: 62 %

Procedure:
To a solution of N,N-dimethyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethanamine (1.0 g, 3.58 mmol) in methanol (30 mL) was added activated carbon (1.0 g), iron (III) chloride (0.120 mg, 0.2 equiv.) and hydrazine hydrate (0.800 mL, 25 mmol, 7.0 equiv.). The resulting slurry was warmed to 60° C. and maintained overnight. The next morning the reaction was filtered, taken to a residue under reduced pressure, and partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulfate. Volatiles were removed and the derived 1-[(dimethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine was isolated as a white solid of sufficient purity for use in subsequent transformations (0.550 g, 2.20 mmol, 62% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 6 H), 2.95 (t, J=8.43 Hz, 2 H), 3.11 (s, 2 H), 3.68 (s, 3 H), 4.05 (t, J=8.25 Hz, 2 H), 4.61 (s, 2 H), 6.68 (s, 1 H), 7.53 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.Cl.[NH:17]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)=[N:20][N:19]=[N:18]1.C([O-])(=O)C.[Na+]>C(O)CCC.CO>[NH:20]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:2]3[C:11]4[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=4[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=3)=[CH:30][CH:29]=2)=[N:17][N:18]=[N:19]1
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CCCC2
Reactant: NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCCCO
Product: FC(F)(F)c1nc2c(c(NCc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)n1)CCCC2
Temperature: 25 °C
Yield: 49.8 %

Procedure:
To 10 mL of a 5:1 mixture of n-butanol/methanol were added 1.42 g of 4-chloro-5,6,7,8-tetrahydro-2-trifluoromethylquinazoline, 1.73 g of N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amine hydrochloride and 2.7 g of sodium acetate. The resulting mixture was heated at reflux for 5 days and then cooled to room temperature. All solvents were removed by evaporation and the resulting residue was purified on silica to yield 1.35 g (50%) of the desired product. The compound was characterized as its potassium salt: 1H NMR (DMSO-d6, 400 MHz) δ 7.78 (t, J=6.0 Hz, 1H), 7.50 (m, 1H), 7.32 (m, 3H), 7.15 (m, 2H), 7.03 (m, 2H), 4.57 (d, J=6.0 Hz, 2H), 2.61 (m, 2H), 2.38 (m, 2H, 1.75 (m, 4H); negative FAB-MS m/e 488(M-H), 450(M-K). Anal. calcd for C23H19F3KN7.0.5H2O: C, 55.41; H, 4.04; N, 19.67. Found: C, 55.66; H, 4.09; N, 19.46.
Reaction SMILES: C(OC(COC(=O)C)CNC([C:10]1[C:15](I)=[C:14]([NH2:17])[C:13](I)=[C:12](C(NCC(OC(=O)C)COC(=O)C)=O)[C:11]=1I)=O)(=O)C.[O:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44](Cl)=[O:45]>CN(C)C(=O)C>[O:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([NH:17][C:14]1[CH:15]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:45]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reactant: O=C(Cl)C1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccccc1)c1ccco1
Reaction time: 0.5 h

Procedure:
To a stirred solution of N,N'-bis[2,3-bis (acetyloxy)propyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (8.73 g, 10 mmol) (prepared as described in EP 431,838) in N,N-dimethylacetamide (30 mL), was added in drops tetrahydrofuran-2-carbonyl chloride (1.8 g, 13 mmol) (prepared as in part A of Example 3) at 0°-5° . After the addition, the mixture was stirred at 0°-5° for 0.5 hour, then at room temperature for 20 hours. Nitrogen gas was purged through the solution for 0.25 hour, and the N,N-dimethylacetamide was removed in vacuo at 40° . The residue was dissolved in ethyl acetate (200 mL), and the solution was washed successively with cold aqueous sodium bicarbonate (2×50 mL), water (2×50 mL) and saturated sodium chloride (2×50 mL). After drying over sodium sulfate, the solvent was removed in vacuo to obtain the title B furanilide as an off-white foamy material (9.27 g, crude). The crude product (7.2 g), upon purification by column chromatography over silica gel (mobile phase: hexane/ethyl acetate) furnished N,N'-bis[2,3-bis(acetyloxy)propyl]2,4,6-triiodo-5-[[(tetrahydro-2furanyl)carbonyl]amino]-1,3-benzenedicarboxamide (6.19 g), m.p. 101°-104°.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)[CH:9]=[C:8]([C:18]([O:20]C)=[O:19])[C:7]=2[C:6]([CH3:22])=[CH:5]1)([CH3:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)[CH:9]=[C:8]([C:18]([OH:20])=[O:19])[C:7]=2[C:6]([CH3:22])=[CH:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2nnn[nH]2)cc2c1c(C)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn(C(C)C)c2cc(-c3nnn[nH]3)cc(C(=O)O)c12
Temperature: 60 °C
Reaction time: 48 h
Yield: 101 %

Procedure:
To a stirred solution of methyl 1-isopropyl-3-methyl-6-(1H-tetrazol-5-yl)-1H-indole-4-carboxylate (0.27 g, 0.902 mmol) in MeOH (15 mL) and tetrahydrofuran (5 mL) was added 1N NaOH (5 mL, 5.00 mmol). The reaction was heated to 60° C. and stirred for 48 hr. LCMS showed that the reaction was complete. The reaction was concentrated to near dryness under vacuum, acidified with 1 N HCl (5 mL), triturated, filtered and washed with a small volume of water, and dried under vacuum to give the product 1-isopropyl-3-methyl-6-(1H-tetrazol-5-yl)-1H-indole-4-carboxylic acid (0.26 g, 0.911 mmol, 101% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (br. s., 1H), 8.36 (d, J=1.5 Hz, 1H), 8.13 (d, J=1.3 Hz, 1H), 7.65 (s, 1H), 4.85 (quin, J=6.6 Hz, 1H), 2.36 (s, 3H), 1.50 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 286.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]I.[H-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: Cn1ccc2c(OCc3ccccc3)cccc21

Procedure:
Compounds of Formula I can be prepared as illustrated by exemplary reaction in Scheme 1. Reaction of 4-benzyloxy-indole with MeI in the presence of a base such as NaH produced 4-benzyloxy-1-methyl-indole. The benzyl protecting group was removed by hydrogenation to give the 4-hydroxy-1-methyl-indole. Reaction of 4-hydroxy-1-methyl-indole with an aryl-aldehyde such as 5-bromoveratraldehyde and malononitrile in the presence of a base such as piperidine produced the substituted 7-methyl-pyrrolo[2,3-h]chromene.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13].[OH-].[Na+]>C(O)C>[C:1]1([S:7][CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCBr
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ClCCCCSc1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
11 g (0.1 mol) of thiophenol and 18.9 g (0.11 mol) of 1-bromo-4-chlorobutane are mixed at ordinary temperature in a 250 ml flask equipped with a condenser, a thermometer and a dropping funnel. 100 ml of ethanol are added, the mixture is heated to 40° C and 20 ml of 5N NaOH are then added dropwise at this temperature. The speed of addition of the sodium hydroxide is regulated so as to have a reaction medium of neutral pH. When the addition is complete, the reactants are left in contact at 40° C for 3 hours, the alcohol is then evaporated, the oil is extracted with ether and the ether solution is washed with 2N NaOH and then with water. Thereafter the organic phase is dried over MgSO4, the ether is evaporated and a yellow oil ia obtained, which crystallises from ethanol. (18.4 g; 0.092 mol; yield: about 92%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=C.C(N(CCCC)CCCC)CCC>CC1C=CC(C)=CC=1>[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=Cc1ccccc1
Yield: 85.8 %

Procedure:
0.095 g (2.5×10-4 mols) of diacetato-bipyridylpalladium(II), 2.88 ml (25 millimols) of benzoyl chloride, 3.39 ml (31.25 millimols) of ethyl acrylate and 5.96 ml (25 millimols) of tri-n-butylamine in 50 ml of p-xylene, are stirred for 3 hours at 120° C. Working up as described in the preceding examples affords 3.78 g (86% of theory) of ethyl cinnamate.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[CH:13][C:12]=1[CH3:31]>C1COCC1>[F:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]4=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]4[CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)=[CH:13][C:12]=1[CH3:31]
Reactant: Cc1cc(Oc2ccc(-c3cccnc3N)cc2)ccc1F
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)ccc1F
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 245 mg) in THF (dry) (15 mL) was added 2-chloroethanesulfonyl chloride (0.386 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(4-fluoro-3-methylphenoxy)phenyl)pyridin-2-amine (360 mg) in THF (dry) (20 ml) was added at 0° C. and the mixture was stirred at room temperature for 5 hr. The mixture was quenched with water at 0° C. Water, EtOAc and IPE were added and the precipitates were collected, washed with water/EtOAc, dried in vacuo to give the title compound (359.2 mg) as a white solid. A part of this was recrystallized from MeCN/IPE.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:27][O:26][C:16]3[CH:17]=[CH:18][C:19]4[C:20](=[O:25])[CH:21]=[CH:22][O:23][C:24]=4[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[NH4+].[NH4+]>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:27][O:26][C:16]3[CH:17]=[CH:18][C:19]4[C:20](=[O:25])[CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(=O)ccoc4c3O2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4c(c3O2)OCCC4=O)cc1

Procedure:
0.50 g (1.28 mmole) of [(2R)-7-oxo-2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-2-yl]methyl 4-methylbenzenesulfonate in methanol was added to a round bottom flask containing 0.40 g of 10% palladium on carbon under a stream of nitrogen, ammonium carbonate was then added and the heterogeneous mixture was heated to reflux for 2.5 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuum and the residue column chromatographed on silica gel with 0.5% methanol/methylene chloride as eluant to give 0.30 g (61%) of the (R)-enantiomer of the title compound as a white foam. 1H (CDCl3) doublet 7.8 δ (2 H); doublet 7.5 δ (1 H); doublet 7.4 δ (2 H); doublet 6.6 δ (1 H); triplet 4.6 δ (2 H); multiplet 4-4.5 δ (5 H); triplet 2.8 δ (2 H); singlet 2.5 δ (3 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:21]([O:20][C:18]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Cc1ccccc1CN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1ccccc1CNC(=O)OCc1ccccc1

Procedure:
To a solution of 3.0 g (9.64 mmol) tert-butyl [2-(aminomethyl)phenyl]acetate in 100 mL methylene chloride cooled to 0° C. was added 0.825 ml (5.78 mmol) benzyl chloroformate followed by 1.47 g (12.05 mmol) of 4-dimethylaminopyridine and a second 0.825 ml (5.78 mmol) portion of benzyl chloroformate. After 30 min the reaction was washed with 10% potassium hydrogen sulfate (aq) (2×3 mL), water (1×30 mL), and brine (1×30 mL), dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The resulting crude oil (3.69 g) was flash chromatographed on silica gel (15% ethyl acetate in hexane) to give tert-butyl [2-({[(benzyloxy)carbonyl]amino}methyl)phenyl]acetate as a colorless oil: 1H NMR (CDCl3, 400 MHz): δ 7.38-7.30 (m, 5H), 7.28-7.21 (m, 4H), 5.40 (br s, 1H), 5.12 (s, 2H), 4.40 (d, 2H, J=5.5 Hz), 3.61 (s, 2H), 1.41 (s, 9H); MS (Electrospray): M+Na=378.1; TLC Rf=0.30 (15% ethyl acetate in hexane).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][CH:8]([Cl:18])[CH:9]1[CH:14]2[CH:12]([C:13]2([CH3:16])[CH3:15])[C:11](=[O:17])[O:10]1.Cl>CS(C)=O.O>[Cl:7][C:8]([Cl:18])=[CH:9][C@H:14]1[C:13]([CH3:16])([CH3:15])[C@H:12]1[C:11]([OH:17])=[O:10]
Reactant: CC1(C)C2C(=O)OC(C(Cl)Cl)C21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium tertiary butoxide (0.45 mmol) was added to a solution of 4-dichloromethyl-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one (0.16 mmol) in dry dimethylsulphoxide (0.4 ml) and stirred at room temperature for 1/2 hour. The solution was then diluted with water, acidified with concentrated hydrochloric acid and extracted with CDCl3. NMR analysis showed a virtually quantitative yield of the desired cis acid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.F[C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:34]([N+:35]([O-:37])=[O:36])=[C:33]([CH:32]=2)[NH:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[N:26][CH:27]=1
Reactant: Cc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)nc1
Reactant: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)c2)nc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 73.6 %

Procedure:
To a flask containing (4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methanamine (107 g, 406 mmol) and 2-((3-fluoro-4-nitrophenoxy)methyl)-5-methylpyridine (114 g, 406 mmol) in acetonitrile (900 mL) was added DIPEA (106 mL, 610 mmol). The stirred mixture was then warmed to 80° Celsius and held for 7 h. After cooling to RT, the resulting slurry was diluted with acetonitrile (300 mL), filtered and the resulting solids were washed with acetonitrile (200 mL). The solids were dried in a vacuum oven at 75° Celsius for 3 h to give the title compound (147.5 g, 73%). MS (ESI): mass calcd. for C27H22F3N3O3, 493.2; m/z found, 494.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.71 (bs, 1H), 8.38 (s, 1H), 8.17 (d, J=9.5, 1H), 7.69 (s, 4H), 7.58 (d, J=7.8, 2H), 7.49 (d, J=7.8, 1H), 7.43 (d, J=7.8, 2H), 7.29 (d, J=8.0, 1H), 6.35 (d, J=9.6, 1H), 6.29 (s, 1H), 5.13 (s, 2H), 4.54 (d, J=5.7, 2H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].O[NH:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=3)[N:26]=2)[CH2:17][CH2:16]1)=[NH:14].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:14]=[C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:22]=[CH:23][C:24]5[N:25]([C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=5)[N:26]=4)[CH2:19][CH2:20]3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: N=C(NO)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4noc(-c5cccc(Cl)c5)n4)CC3)nn12
Temperature: 150 °C
Reaction time: 1 h

Procedure:
3-Chlorobenzoyl chloride (92 mg, 0.53 mmol) was added to a stirred partial solution of N-hydroxy-4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboximidamide (165 mg, 0.5 mmol) and DIPEA (97 mg, 0.75 mmol) in THF (3 mL). The reaction mixture became a clear solution over 30 minutes and LCMS after 1 hour showed complete initial acylation. The reaction mixture was heated at 150° C. for 15 minutes by microwave after which LCMS showed complete cyclisation to the desired product. The reaction mixture was evaporated and the residue was boiled briefly with ethanol, cooled and filtered off to give 6-[4-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (104 mg, 46%) as a crystalline powder.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][CH:34]([CH2:37][NH2:38])[CH2:33][CH2:32]1>>[C:2]1([C:1]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:26]=[CH:25][CH:24]=[C:21]([CH2:22][NH:38][CH2:37][CH:34]4[CH2:35][CH2:36][NH:31][CH2:32][CH2:33]4)[CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:27]([F:30])([F:28])[F:29])=[O:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CCNCC1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(CNCC2CCNCC2)c1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and C-piperidin-4-yl-methylamine according to the procedure of Example 66. MS (ESI) m/z 504.