Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][S:10]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:29]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:28]=[C:27]([C:36]([F:39])([F:38])[F:37])[CH:26]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11]>>[Br:1][C:26]1[C:27]([C:36]([F:39])([F:38])[F:37])=[N:28][N:29]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([S:10]([CH3:9])(=[O:11])=[O:12])[CH:14]=2)=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Product: CCOC(=O)Cn1nc(C(F)(F)F)c(Br)c1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1

Procedure:
Following bromination with N-bromosuccinimide, the title compound 37 is prepared starting from ethyl 2-(5-(3′-(methylsulfonyl)biphenyl-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate 36.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[N:13]1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([NH:13][S:20]([CH3:19])(=[O:22])=[O:21])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: c1ccncc1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(S(N)(=O)=O)c(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
2,5-Diamino-benzenesulfonamide (288 mg, 1.5 mol, prepared according to the procedure as described in Goldfarb A. R. et. al., J. Amer. Chem. Soc. 1943, 65, 738) in dichloromethane (5 mL) and pyridine (5 mL) at 0° C. was treated dropwise with methanesulfonyl chloride (119 μL, 1.5 mmol) over 3 minutes. The reaction mixture was warmed to 25° C. and stirred for 18 hours and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with methanol in dichloromethane to yield the title compound (68% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.21 (m, 1H), 7.45 (d, J=2.57 Hz, 1H), 7.29 (s, 2H), 7.13 (dd, J=8.64, 2.39 Hz, 1H), 6.78 (d, J=8.82 Hz, 1H), 5.80 (s, 1H), 3.39 (s, 1H), 2.87 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)[CH2:4]1.[CH:22](O)=[O:23]>O>[O:8]=[C:6]1[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)[CH2:4][C@H:3]([CH2:2][NH:1][CH:22]=[O:23])[O:7]1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: O=CO
Solvent: O
Product: O=CNC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 115 °C

Procedure:
In a four neck round bottom flask charged with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one free base (50 g) toluene (350 ml) and formic acid (21.63 g). Reaction mass then heated azeotropically to 110-120° C. employing dean-stark apparatus for 3 to 4 h. (water removed azeotropically) Reaction mass is cooled to 25 to 30° C. Obtained solid is filtered off and washed by toluene.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]([C:26]1[C:31]([O:32][CH3:33])=[N:30][C:29]([CH3:34])=[CH:28][N:27]=1)[S:9]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=2)=[N:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[O:7])[CH:2]([CH3:4])[CH3:3].[Br-].[C:36]([CH2:39][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:38])=[O:37].[OH-].[Na+].[CH2:61](Cl)Cl>O>[CH2:1]([O:5][C:6]([N:8]([C:26]1[C:31]([O:32][CH3:33])=[N:30][C:29]([CH3:34])=[CH:28][N:27]=1)[S:9]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:39][C:36]([O:38][CH3:61])=[O:37])=[CH:20][CH:19]=2)=[N:14][CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:11])=[O:7])[CH:2]([CH3:3])[CH3:4]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(C=O)cc1
Reactant: ClCCl
Reactant: O=C(O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)C=Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-isobutoxycarbonyl-2-(4-formylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (500 mg) was added to carboxymethyl triphenylphosphonium bromide (429 mg) in a mixture of saturated aqueous sodium hydroxide (1.25 ml) and methylene chloride (4 ml) and stirred vigorously at ambient temperature for 1.5 hours. Water (20 ml) was added and the mixture extracted with dichloromethane (2×20 ml). The combined organic extracts were, washed with water (5 ml), dried (MgSO4) and evaporated. The residue was purified by chromatography on a Mega Bond Elut column, eluting with a gradient of 0-30% ethyl acetate in hexane. Fractions containing the product were combined, evaporated and the residue was triturated with diethyl ether/isohexane (1:1 v/v) and filtered to give N-isobutoxycarbonyl-2-[4-(2-[methoxycarbonyl]vinyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (366 mg), m.p 155°-156° C.; 1H NMR (CDCl3): 0.65 (d, 6 H), 1.7 (septet, 1 H), 2.5 (s, 3 H), 3.82 (s, 3 H), 3.85 (d, 2 H), 3.98 (s, 3 H), 6.48 (d, 1 H), 7.4-7.8 (m , 7 H), 7.9 (s, 1 H), 8.86 (dd, 1 H), 8.98 (dd, 1 H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][CH2:22][NH2:23]>>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH:2]([OH:1])[CH2:3][NH:23][CH2:22][CH2:21][C:17]3[N:16]([CH3:15])[CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Cn1cccc1CCN
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Product: Cn1cccc1CCNCC(O)COc1cccc2[nH]ccc12
Yield: 60 %

Procedure:
The title compound was prepared in similar fashion from 4-(oxiranylmethoxy)-1H-indole and 2-(1-methyl-1H-pyrrol-2-yl)ethylamine in 60% yield. FDMS m/e=313. mp 105°-106°.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:10])=[CH:28][CH:27]=1
Reactant: O=C(/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1ccc(F)cc1)c1ccc(F)cc1)NCCCCc1cccnc1
Yield: 93.8 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-fluorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (15 g) and 3-pyridinebutanamine (5.53 g) in tetrahydrofuran (60 mL) was stirred for 1.5 hours at room temperature and was worked up in the usual manner. The crude amide was crystallized from ethyl acetate-hexane (2x) to give 14.45 g of (E)-5,5-bis(4-fluorophenyl)-N-[4-(3-pyridinyl) butyl]-2,4-pentadienamide mp 155°-156° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH2:20][OH:21])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(-c2cccs2)s1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(Cl)s2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a solution of 5-chloro-[2,2′]bithiophenyl (3.00 g, 14.9 mmol) in 30 mL of THF at 0° C. is added n-BuLi (9.8 mL of a 1.6M solution in hexanes, 15.7 mmol) dropwise. DMF (2.30 mL, 30 mmol) is added dropwise and the resulting solution is heated at reflux for 1 hour. The solution is diluted with H2O and extracted with Et2O. The organic layer is washed with H2O and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude aldehyde is dissolved in 40 mL of anhydrous MeOH and sodium borohydride (0.85 g, 22.5 mmol) is added portionwise. The mixture is stirred at room temperature for 10 min, then quenched with water. The mixture is diluted with Et2O and the layers separated. The organic layer is washed with H2O, then dried over MgSO4, filtered and concentrated to yield the title compound (2.23 g, 9.66 mmol) which is used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ6.95 (d, 1H), 6.90 (m, 2H), 6.86 (d, 1H), 4.82 (s, 2H), 1.88 (bs, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH:18](C(OCC)=O)[C:19]([O:21]CC)=[O:20]>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][CH:18]([CH3:17])[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Product: CC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O

Procedure:
A 22 g quantity of 4-benzyloxybenzyl chloride was treated with diethyl methylmalonate anion following the procedure in Example 8. The alkylated methylmalonate was saponified and decarboxylated following the same procedure to obtain 18.06 g of 2-(4-benzyloxybenzyl)propionic acid, m p. 93°-95° C. A 3.6 g quantity of this acid was treated with 5,6-diamino-1,3-dipropyluracil to obtain the amide and was cyclized following the procedure in Example 7 to obtain 1.46 g of material which was recrystallized from 5% ethyl ether in hexane to yield 0.72 g of 3,7-dihydro-8-[methyl-2-(4-benzyloxyphenyl)ethyl]-1,3-dipropyl-1H-purine-2,6-dione, m.p. 124°-126° C. A 260 mg quantity of 3,7-dihydro-8-[methyl-2-(4-benzyloxyphenyl)ethyl]-1,3-dipropyl-1H-purine-2,6-dione was dissolved in 20 ml of methyl alcohol and treated with a catalytic amount of 5% palladium on charcoal. This was placed under an atmosphere of hydrogen for 2 hours with stirring. It was then filtered through Celite and the filtrate concentrated under vacuum. The residue was purified by radial chromatography (50% ethyl acetate in hexane, 4 mm plate) to yield 182 mg of material which was triturated with 5% ethyl ether in hexane to yield, after drying under high vacuum at 39° C. for 3 hours, 162 mg of 3,7-dihydro-8-[methyl-2-(4-hydroxyphenyl)ethyl]-1,3-dipropyl-1H-purine-2,6-dione, m.p. 218°-220° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[O:23][CH3:24])=[C:10]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:9]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:7][C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:18][C:17]=2[O:23][CH3:24])=[C:10]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:9]=1
Reactant: COC(=O)CBr
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(OCC(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl bromoacetate (57 ul) was added to a mixture of the product from step (v) (0.2 g) and K2CO3 (0.251 g) in DMF (10 ml) and the mixture stirred at rt for 24 h. The mixture was partitioned between EtOAc/water, the organics separated, dried and evaporated under reduced pressure. The residue was purified by RPHPLC to afford the title compound, 0.057 g
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([Cl:18])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)c(C(F)(F)F)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)Cl)c(C(F)(F)F)n1
Reaction time: 1.5 h

Procedure:
A solution of 0.45 g of 6-methyl-2-trifluoromethylpyridin-3-ylcarboxyi ic acid in 20 ml of dichloromethane is charged initially, 3 drops of dimethylformamid c are added and the mixture is subsequently treated with 1.6 ml of oxalyl chloride. After the intensive evolution of gas has ceased, the mixture is kept at a bath temperature of 40° C. for another 1.5 hours and then evaporated. The crude product (0.56 g) that remains as residue can be directly reacted further. 1H NMR (CDCl3, ppm): 8.20 (1H,d); 7.51 (1H,d); 2.65 (3H, s).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.Cl[C:9]1[C:14]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.Cl>CN(C)C=O.C(OCC)(=O)C>[CH:3]1([CH2:6][O:7][C:9]2[C:14]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1
Reactant: OCC1CC1
Reactant: NS(=O)(=O)c1cccnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cccnc1OCC1CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
11.99 g of a 55% dispersion of sodium hydride are suspended in 40 ml of dimethylformamide and 13.04 ml of cyclopropylmethanol are added dropwise at 10° C. under a nitrogen atmosphere. The mixture is stirred for 15 minutes and then a solution of 21.16 g of 2-chloropyridin-3-ylsulfonamide in 40 ml of dimethylformamide is added dropwise. The reaction mixture is stirred for 30 minutes at 35°-40° C. and then taken up in a mixture of 275 ml of ethyl acetate, 275 ml of ice-water and 137.5 ml of 2N hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with 3×100 ml of ethyl acetate. The combined organic phases are washed with 4×100 ml of water, dried, concentrated by evaporation and the residue is triturated with ether/hexane (2:1). The crystals so obtained are isolated and dried, affording 22.25 g of 2-cyclopropylmethoxypyridin-3-ylsulfonamide with a melting point of 121°-122° C.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5]C=CC=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C(N)C(C)C>C(O)(=O)C>[CH2:1]([N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[N:9]=[CH:8]1)[CH:6]([CH3:5])[CH3:24]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Solvent: CC(C)CN
Product: CC(C)Cn1cnc2c(-c3ccccc3)csc2c1=O
Yield: 57 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), isobutylamine (0.099 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 69.7 mg (0.25 mmol, 57% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N([CH2:15][CH3:16])CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:55])C=[C:31]([CH2:37][C:38]2[C:43]([C:44](O)=[O:45])=[C:42]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:41]=[CH:40][CH:39]=2)[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:55])[C:15]([CH3:16])=[C:31]([CH2:37][C:38]2[C:43]([C:44]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:45])=[C:42]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:41]=[CH:40][CH:39]=2)[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(OCc3ccccc3)c2C(=O)O)=CC1=O
Reactant: COc1ccc(N)cc1
Reactant: CCN(CC)CC
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(OCc3ccccc3)c2C(=O)Nc2ccc(OC)cc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
p-Methoxyaniline (13 mg, 0.1056 mmol), triethylamine (15 mg, 0.1485 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (24 mg, 0.1420 mmol) were added to a methylene chloride solution (3 ml) of 6-(5,6-dimethoxy-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (29 mg, 0.0687 mmol) and the resulting solution was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (20 mg, 0.0687 mmol, 55%).
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[C:8]2[N:9]([C:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([C:22](OC)=[O:23])[CH2:18][CH2:17]3)=[N:14][CH:15]=2)[CH:10]=[CH:11][N:12]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)(=O)C>[Cl:6][C:7]1[C:8]2[N:9]([C:13]([C@H:16]3[CH2:17][CH2:18][C@H:19]([CH2:22][OH:23])[CH2:20][CH2:21]3)=[N:14][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A THF solution (1.00 L) of trans-methyl 4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate(29.70 g, 101.1 mmol) was cooled to −78° C. and was charged with LAH (1M in THF, 25.3 mmol, 25.3 mL) dropwise. After 30 min., the reaction mixture was charged with additional LAH (25.3 mmol) at −78° C. and then, allowed to stir at −78° C. for 1.5 h. The reaction was slowly warmed up to rt and stirred for additional 30 min. Ethyl acetate, Na2SO4.10H2O, and silica gel were added to the reaction mixture and concentrated in vacuo to give an orange solid. The crude mixture was purified by a silica gel glass column chromatography (eluted with 2:3 EtOAc/DCM to 100% EtOAc) to obtain the title compound as a slightly yellow-tinted white solid; 1H NMR (CDCl3, 400 MHz) δ 1.14-1.30 (m, 2H), 1.61-1.75 (mc, 1H), 1.84 (ddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.98-2.13 (m, 4H), 2.19 (s, br, —OH), 2.94 (tt, J=11.6, 3.2 Hz, 1H), 3.56 (d, J=6.0 Hz, 2H), 7.31 (d, J=5.2 Hz, 1H), 7.64 (dd, J=5.2, 1.2 Hz, 1H), 7.79 (d, J=0.8 Hz, 1H); MS (ES+): m/z 266.21/268.17 (100/89) [MH+]. HPLC: tR=2.38 min (OpenLynx, polar13 5 min). MS (ES+): m/z 266.21 (100) [MH+], 268.17 (80) [MH+2}, 289.18 (20) [MH+3]; tR(polar-5 min/openlynx) 2.36 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]([CH3:22])[C:20]#[N:21])[CH:15]=[CH:16][C:17]=1O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:17]3[CH:16]=[CH:15][C:14]([CH:19]([CH3:22])[C:20]#[N:21])=[CH:13][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CC(C#N)c1ccc2oc(Nc3ccc(Cl)cc3)nc2c1

Procedure:
4-chlorophenylisocyanate (3.1 g.) was slowly added to a stirred solution of 2-(3-amino-4-hydroxyphenyl propionitrile (3.3 g) in xylene (35 ml.) at room temperature. When the addition was complete p-toluenesulphonic acid (250 mg.) was added, and the solution was heated under reflux using a Dean and Stark apparatus. On cooling, the solution was washed with aqueous sodium bicarbonate solution and evaporated to dryness. The residue was recrystallised to give 2-[2-(4-chloroanilino)-5-benzoxazolyl] propionitrile as a creme solid which was characterised by n.m.r. spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:24][NH:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([N:25]([CH3:26])[CH3:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: CNC
Product: COc1ccc(-c2cc(N(C)C)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (140 mg, 0.43 mmol) and a 40% (W/V) aqueous solution of dimethylamine were reacted as starting materials at 45° C. for 30 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless prisms (139 mg, 96.5%). Melting point: 109.6-110.7° C. (ethyl acetate-hexane).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51]([CH3:54])(=[O:53])=[O:52]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[S:51]([CH3:54])(=[O:53])=[O:52])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: CS(=O)(=O)c1ccccc1CBr
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nnn(Cc3ccccc3S(C)(=O)=O)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(methylsulfonyl)benzene and isolated as white solid. MS (m/e): 443.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]2)[CH:20]=[N:19][CH:18]=1.[F:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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.O>[F:37][C:38]1[CH:43]=[C:42]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:25][CH2:24]3)[CH:20]=[N:19][CH:18]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5cccc(F)c5)cc34)n2)CC1
Temperature: 140 °C
Yield: 57.9 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.200 g, 0.359 mmol), 3-fluorophenylboronic acid (0.072 g, 0.515 mmol, Aldrich), Na2CO3 (0.210 g, 1.981 mmol, J. T. Baker) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.022 g, 0.031 mmol, Strem). Dioxane (3 mL) and water (1 mL) were added and the reaction mixture was sealed under argon and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 15 min. The mixture was partitioned between EtOAc/water. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, (40 gram)) eluting with 2M NH3 in MeOH:DCM (0:1→1:49) to give 119 mg of tert-Butyl 1-(6-(5-(3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 573.2 (M+1). A solution of tert-butyl 1-(6-(5-(3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.119 g, 0.208 mmol) in HCl, 5-6 N in IPA (5.00 mL, 25.00 mmol) and water (0.5 mL) was heated at 80° C. for 2.5 h. The reaction mixture was cooled to RT and the solid was filtered and washed with IPA. The material was dissolved in DMSO and purified by reverse-phase HPLC (Gilson; Gemini-NX 10μ C18 110 A AXIA, 100×50 mm column) eluting with 0.1% TFA-H2O:0.1% TFA ACN (9:1→1:9). The fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX II cartridge eluting with MeOH then 2M NH3 in MeOH to give the title compound as a yellow crystalline solid. MS (ESI, pos. ion) m/z: 389.1 (M+1).