Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[NH2:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[F:17][C:18]([F:29])([F:28])[C:19]1[S:20][CH:21]=[C:22]([C:24](=[O:27])[CH2:25]Br)[N:23]=1>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:15][CH2:25][CH:24]([OH:27])[C:22]2[N:23]=[C:19]([C:18]([F:29])([F:28])[F:17])[S:20][CH:21]=2)[CH3:16])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N)cc1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-(4-carbomethoxymethoxyphenyl)-1-methyl-ethanamine with 2-trifluoromethyl-4-bromoacetyl-thiazole, followed by reduction and purification of the base on a silica gel column with methylene chloride/methanol =20:1 as eluant.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])C)[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN(C4(C(OC)=O)CC4)C3=O)=CC=2)=CC=1.[Cl:58]C1C=CC(C(Cl)=O)=CC=1>>[Cl:58][C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([C:26]5([C:27]([O:29][CH3:30])=[O:28])[CH2:33][CH2:31]5)[C:22]4=[O:25])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[O:8])=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CC1
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(Cl)cc5)cc4)cc3C2=O)CC1
Yield: 95 %

Procedure:
The compound of example 587 was prepared analogous to compound of example 97 by reaction of compound of example 584 with 4-chloro benzoyl chloride.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@:8]([S:36]([CH3:39])(=[O:38])=[O:37])([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[C:9]([NH:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)=[O:10].Br[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>COCCOC.CO.C(OCC)(=O)C>[C:24]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][C@@:8]([CH3:7])([S:36]([CH3:39])(=[O:38])=[O:37])[C:9]([NH:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[O:10])=[CH:26][CH:25]=1
Reactant: CC1(C)OB(c2ccc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2)OC1(C)C
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@](CCc1ccc(-c2ccccc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Trisdibenzylidine dipalladium (0.19 g, 0.21 mmol) was added to a mixture of potassium carbonate (1.45 g, 10.5 mmol, 5.0 equiv), (2R)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanamide, which may be prepared as in Preparation 8C (1.0 g, 2.1 mmol) and bromobenzene (0.26 mL, 2.5 mmol) in 1,2-dimethoxyethane-methanol (8.0 mL, 1:1). The reaction was heated to 80° C. and allowed to stir overnight. The reaction was diluted with ethyl acetate (60 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (heptane/ethyl acetate system) to provide the title compound as a tan gum-like material (72 mg, 8%). MS (LCMS) m/z 430.8 (M−1).
Reaction SMILES: ClCCl.C(Cl)CCl.[CH3:8][S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][C:14]1[CH:15]=[C:16]([C:31]2[CH:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=2)[CH:17]=[C:18]([NH:20][C:21]2[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=2)[CH:19]=1.CN([CH:43]=[O:44])C>CN(C1C=CN=CC=1)C.[Cl-].[NH4+]>[CH3:8][S:9]([NH:12][C:37]([C:34]1[CH:33]=[CH:32][C:31]([C:16]2[CH:17]=[C:18]([NH:20][C:21]3[N:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][N:22]=3)[CH:19]=[C:14]([CH3:13])[CH:15]=2)=[CH:36][N:35]=1)=[O:38])(=[O:11])=[O:10].[C:43]([OH:44])([C:27]([F:30])([F:29])[F:28])=[O:10]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(=O)O)nc2)c1
Reactant: CS(N)(=O)=O
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(=O)NS(C)(=O)=O)nc2)c1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dichloromethane (670 μL), EDC (38 mg, 0.20 mmol), methylsulfonamide (25 mg, 0.27 mmol) and DMAP (1.6 mg, 0.013 mmol) were added to 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carboxylic acid (50 mg, 0.13) and the reaction was allowed to stir for 16 hours at room temperature. DMF (500 μL) was added to the reaction and stirred overnight at room temperature. The reaction was then diluted with aqueous saturated ammonium chloride and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10-100% acetonitrile/water with 0.1% TFA) to afford N-(methylsulfonyl)-5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carboxamide as a TFA salt. MS ESI calc'd for C19H17F3N5O3S [M+H]+ 452. found 452. 1H NMR (500 MHz, DMSO-d6) δ 10.45-10.28 (m, 1H), 9.05-8.91 (m, 1H), 8.92-8.78 (m, 1H), 8.39-8.25 (m, 1H), 8.25-8.12 (m, 1H), 8.12-8.02 (m, 1H), 7.71-7.57 (m, 1H), 7.44-7.21 (m, 1H), 3.39 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH:13][C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]5[CH:29]=[CH:28][C:27]([NH:30]C(OC(C)(C)C)=O)=[CH:26][CH:25]=5)=[CH:19][N:18]=4)=[O:15])[C@H:7]3[C:6]=2[C:5]([F:38])=[CH:4][CH:3]=1.Cl.CC(O)=O.CCO.C(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH:13][C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]5[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=5)=[CH:19][N:18]=4)=[O:15])[C@H:7]3[C:6]=2[C:5]([F:38])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)N[C@@H]3[C@@H]4COc5c(F)ccc(F)c5[C@@H]43)nc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(Oc2ccc(NC(=O)N[C@@H]3[C@@H]4COc5c(F)ccc(F)c5[C@@H]43)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
Dried N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(4-(N-t-butoxycarbonylamino)phenoxy)-2-pyridinyl]urea (242 mg, 0.46 mmol) was dissolved in methylene chloride (2 ml) and then 1M HCl/AcOH (4.6 ml) was added and the reaction solution was stirred for 60 minutes at room temperature. The volatile matters were removed by evaporation. The residue was worked up by extractions between methylene chloride and sat. aq. NaHCO3. The organic phase was dried through sodium sulfate and evaporated. Silica gel column chromatography (1-3% EtOH/methylene chloride gradient) gave 139 mg of pure product as white powder (71% yield).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[F:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3ccc(F)nc3)cc2C1

Procedure:
The title compound was prepared by a similar process to the preparation of Example 1, starting from Intermediate 2 with (6-fluoro-3-pyridinyl)boronic acid, except that, instead of stirring the mixture at conventional reflux for 16 h, the reaction mixture was stirred in a microwave reactor at 160° C. for 20 minutes.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Br)[CH:25]=1>CN(C=O)C.O>[Br:22][CH2:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2)[C:2]1=[O:1]
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Reactant: BrCc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2ccn(Cc3cccc(CBr)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.15 g, 0.74 mmol) in DMF (7.5 mL) was added cesium carbonate (0.72 g, 2.2 mmol) and 1,3-bis(bromomethyl)benzene (0.29 g, 1.1 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 5% EtOAc/DCM) to afford methyl 2-[3-(bromomethyl)benzyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.12 g, 42%). LC-MS: (FA) ES+ 388.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH:1]([CH2:12][C:10](=[CH2:11])[C:9]([OH:14])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=C(C)C(=O)O
Reactant: C=Cc1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: C=C(CC=Cc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
First, 100 g of styrene, 0.033 g of methacrylic acid, and 0.5 g of BPO (benzoyl peroxide) were dissolved in benzene (solvent), and the resulting solution was kept at 80° C. for 3 hours. Then, benzene as solvent was removed, and the styrene-methacrylic acid copolymer was obtained. This copolymer is hereinafter referred to as SMCPa. The content of methacrylic acid as a functional monomer in SMCPa was 0.05 mol %.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30].CCN(C(C)C)C(C)C>C1COCC1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]4[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:6][CH:7]=2)=[O:25])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(Cl)c([N+](=O)[O-])c4)cc3)sc2c1
Yield: 96.8 %

Procedure:
Prepared as described in the Amide Coupling section using 2-(4-aminophenyl)-6-methoxybenzothiazole (0.50 g, 1.95 mmol), 4-chloro-3-nitrobenzoyl chloride (0.43 g, 1.95 mmol) and Hunig's base (0.28 g, 2.15 mmol) in dry THF (20 ml) to give the title compound (0.83 g, 97%) as a yellow solid after work-up.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.CN(C)C=O.[H-].[Na+].[CH2:18]([O:20][CH2:21][CH2:22]Cl)[CH3:19]>C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[N:6]([CH2:19][CH2:18][O:20][CH2:21][CH3:22])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CCOCCCl
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOCCn1c(Cl)nc2ccccc21
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Combine 2-chloro-1H-benzimidazole (21.1.4 g, 138.4 mmol) and dimethylformamide (200 mL). Add portionwise, sodium hydride (24.0 g, 60% in oil, 153.3 mmol). After 15 minutes, add 2-chloroethyl ethyl ether (21.9 g, 201,5 mmol). Heat to 60° C. After 18 hours, cool the reaction mixture and dilute with ethyl acetate. Extract with a saturated aqueous sodium bicarbonate solution, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% ethyl acetate/hexane and then 30% ethyl acetate hexane to give the 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole: Rf =0.74 (silica gel, 7/3 ethyl acetate/hexane).
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.S(=O)(=O)(O)O>C(OCC)(=O)C.C(Cl)Cl>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)NCCCc1ccc2c(n1)NCCC2
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCc1ccc2c(n1)NCCC2

Procedure:
The title compound was prepared by treating the Boc derivative 1-5 with either HCI gas in ethyl acetate as described in U.S. Pat. No. 5,952,341 and WO 99/31061, or with trifluoroacetic acid in methylene chloride, or aqueous sulfuric acid; m.p. 66.0-68.5° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[C:28]([CH3:35])[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:45][C@@H:46]1[NH:51][CH2:50][CH2:49][N:48]([S:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH2:47]1>CN(C=O)C>[F:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([N:51]2[CH2:50][CH2:49][N:48]([S:52]([C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=3)(=[O:53])=[O:54])[CH2:47][C@@H:46]2[CH3:45])=[O:34])=[C:28]([CH3:35])[CH:27]=1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ncc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
HATU (440 mg, 1.16 mmol) was added to a solution of 6-fluoro-4-methyl-3-pyridinecarboxylic acid (supplied by Frontier Scientific) (150 mg, 0.97 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.422 ml, 2.42 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (358 mg, 1.16 mmol) was added and stirring was continued for 1.25 h. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organic layers were concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in hexanes, gave the title compound (432 mg) as a yellow gum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([N:15]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])=[CH:12][C:7]=2[N:6]=[C:5]1[NH:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1.[CH:37]1([CH:43]=O)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.[BH4-].C(OC1C=CC=CC=1C=O)C1C=CC=CC=1>CO.ClCCl>[CH:37]1([CH2:43][NH:1][CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][C:11]([C:13]([N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:20][CH:21]([CH3:22])[CH3:23])=[O:14])=[CH:12][C:7]=3[N:6]=[C:5]2[NH:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=CC1CCCCC1
Reactant: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCN)cc(OC)c1OC
Agent: O=Cc1ccccc1OCc1ccccc1
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCNCC2CCCCC2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
A solution of 1-(2-aminoethyl)-N,N-diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-5-carboxamide (30 mg, 1 eq) and cyclohexanecarboxaldehyde (5 mg, 0.8 eq) in methanol (0.7 ml) is stirred at a temperature of approximately 20° C. for 4 hours. Borohydride resin (48 mg, 2.5 mmol/g, Amberlite®, IRA-400) is added and the mixture is stirred for 18 hours then dichloromethane (0.5 ml) and benzyloxybenzaldehyde Wang resin (37 mg, 3.22 mmol/g, Novabiochem) are added. After stirring overnight, the mixture is filtered and the filtrate is evaporated under reduced pressure in order to produce the expected compound in the form of a beige foam (18 mg, 65%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH:6][CH2:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])[OH:9]>[Sn](F)F>[CH2:1]([O:17][CH2:16][C@@H:14]([C@H:12]([C@@H:10]([C@@H:8]([CH2:7][OH:6])[OH:9])[OH:11])[OH:13])[OH:15])[CH:3]1[O:5][CH2:4]1
Reactant: ClCC1CO1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: F[Sn]F
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)COCC1CO1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 750 ml reactor equipped with reflux condenser, thermometer, stirrer and metering device for epichlorohydrin is charged with 72.9 g (0.4 mol) of sorbitol and 1.25 g (0.008 mol) of tin difluoride in 88.5 g (0.957 mol) of epichlorohydrin, and the charge is heated to 110° C. Then, with stirring, 132.1 g (1.429 mol) of epichlorohydrin are added at a rate of 1.5 ml/min, while keeping the temperature at 110°-115° C. Stirring is continued for a further 8 hours at 125°-130° C. Excess epichlorohydrin is removed by distillation under a water jet vacuum and the residue is diluted with 441 g of methyl isobutyl ketone. With efficient stirring, 142.4 g (1.78 mol) of a 50% solution of sodium hydroxide are added dropwise over 1 hour and the reaction mixture is kept for another 2 hours at this temperature. The reaction mixture is neutralised by addition of dry ice and filtered, and the organic phase is dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is dried under vacuum (2 hours/60° C.), giving 155.2 g of sorbitol glycidyl ether for which the following analytical values are obtained: epoxy value: 5.5 eq/kg; total chlorine content 15.56%; hydrolysable chlorine content 1.09%; viscosity at 40° C.: 2460 mPa.s; average molecular weight Mn (GPC): 658.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[C:22]([O:26][C:27]([NH:29][C:30]12[CH2:37][CH2:36][C:33]([C:38](O)=[O:39])([CH2:34][CH2:35]1)[CH2:32][CH2:31]2)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[S:12]([N:9]1[C:6]2=[N:7][CH:8]=[C:3]([NH:1][NH:2][C:38]([C:33]34[CH2:34][CH2:35][C:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])([CH2:31][CH2:32]3)[CH2:37][CH2:36]4)=[O:39])[N:4]=[C:5]2[CH:11]=[CH:10]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)C45CCC(NC(=O)OC(C)(C)C)(CC4)CC5)cnc32)cc1

Procedure:
The precursor to Example #H.1. 1,3-chloro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)benzene sulfonamide, was prepared as shown in Scheme B. 2-Hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (Preparation #9) and 4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid are reacted following the conditions given in General Procedure A to give tert-butyl 4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)bicyclo[2.2.2]octan-1-ylcarbamate. This hydrazide is cyclized using the conditions given in General Procedure C to afford tert-butyl 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-ylcarbamate. This carbamate is deprotected using General Procedure I to yield 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine. This amine is sulfonylated using the conditions described in General Procedure N to give the precursor to Example #H.1.1. The reaction sequence detailed above is translated in the preparations and examples section to “using A from Preparation #9 and 4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid [Prime Organics], C with TEA, I, N from 3-chlorobenzenesulfonyl chloride”.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][O:8][C:4]=2[CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].[CH:19](OCC)(OCC)OCC>C(O)(=O)C>[N:1]1([C:2]2[CH:14]=[CH:13][C:5]3[CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][O:8][C:4]=3[CH:3]=2)[CH:19]=[N:17][N:16]=[N:15]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)C1COc2cc(N)ccc21
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1COc2cc(-n3cnnn3)ccc21
Temperature: 25 °C

Procedure:
A solution of methyl 6-amino-2,3-dihydro-1-benzofuran-3-carboxylate (2.51 g, 13 mmol), sodium azide (1.01 g, 15.6 mmol) and triethyl orthoformate (5.92 g, 40 mmol) in 30 mL of acetic acid was heated to 100° C. for 3 hrs. After the reaction was completed, the mixture was cooled to ambient temperature and the solvent was removed under vacuum. The residue was diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified with silica gel column chromatograph to give the crude product, then re-crystalization from DCM to give methyl 6-(1H-tetrazol-1-yl)-2,3-dihydro-1-benzofuran-3-carboxylate.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[N:29]([CH:16]1[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of 11 (11.5 g, 31.8 mmol) and sodium azide (4.12 g, 64 mmol) in 250 ml of DMF was heated to 70° C. for 24 hours. After cooling to room temperature the solvent was removed in vacuo and the residue partitioned between chloroform and water. The organics were dried over MgSO4, filtered and the solvent removed in vacuo. The crude product was purified by chromatography on silica gel (8:1 hexane:ethyl acetate) to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10](=[O:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]1([O-])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[C:1]1([C:7]2=[N:8][NH:9][C:10](=[O:12])/[C:11]/2=[C:14]2\[NH:13][C:22]3[C:17]([CH:16]=[CH:15]\2)=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-][n+]1cccc2ccccc21
Reactant: O=C1CC(c2ccccc2)=NN1
Product: O=C1NN=C(c2ccccc2)/C1=C1\C=Cc2ccccc2N1

Procedure:
The title compound was synthesized using 3-phenyl-1H-pyrazol-5(4H)-one and quinoline N-oxide according to the procedure described in Example 23. 1H NMR (400 MHz, DMSO-d6) 8 ppm 7.21 (d, J=9.09 Hz, 1H) 7.50-7.60 (m, 7H) 7.82 (t, J=7.71 Hz, 1H) 7.93 (t, J=6.82 Hz, 2H) 8.33 (d, J=8.84 Hz, 1H); ESI-MS: m/z calc'd for C18H13N3O 287.32. found 288.3 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3([CH3:18])[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]3)=[N:10][C:5]2=[N:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][C:21]=1[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]4([CH3:18])[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]4)=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:22][C:21]=1[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Reactant: CC1(C)OCC(C)(c2ccn3c(Br)cnc3n2)O1
Product: CC1(C)OCC(C)(c2ccn3c(-c4ccc(F)c(-c5cccnc5)c4)cnc3n2)O1

Procedure:
3-Bromo-7-(2,2,4-trimethyl-[1,3]dioxolan-4-yl)imidazo[1,2-α]pyrimidine was coupled with 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine as described in Example 65 to give 3-[4-fluoro-3-(pyridin-3-yl)phenyl]-7-(2,2,4-trimethyl-[1,3]dioxolan-4-yl)imidazo[1,2-α]pyrimidine as an orange oil: δH (400 MHz, d6-DMSO) 1.33 (3H, s), 1.47 (3H, s), 1.59 (3H, s), 4.08 (1H, d, J 9), 4.49 (1H, d, J 9), 7.31 (1H, d, J 7), 7.54-7.59 (2H, m), 7.77-7.81 (1H, m), 7.94 (1H, dd, J 7 and 2), 8.01 (1H, s), 8.09-8.12 (1H, m), 8.65 (1H, dd, J 5 and 2), 8.89 (1H, s), 9.08 (1H, d, J 7).