Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1.[OH-].[Na+]>CN(C=O)C.O>[Br:19][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:18]=1
Reactant: Brc1cncc(Br)c1
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.3 %

Procedure:
To a stirred suspension sodium hydride (3.0 g of 80% in mineral oil, 100 mmol) in DMF (95 mL) in an ice water bath, 4-methoxyphenol (12.2 g, 96 mmol) was added slowly under a nitrogen atmosphere. The resulting mixture was warmed to ambient temperature and stirred for 1 h. 3,5-Dibromopyridine (15.6 g of 98%, 65 mmol) was added and the mixture was then heated at 85° C. (bath temperature) for 32 h. The mixture was cooled, diluted with water (120 mL), poured into 5N sodium hydroxide (15 mL), and extracted with ether (3×150 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation, to give a light yellow oil (21.9 g). The oil was diluted with ethanol and rotary evaporated (twice) to remove residual DMF and then diluted with ether (50 mL) and suction filtered to remove un-reacted 3,5-dibromopyridine. Rotary evaporation and high vacuum treatment left a lard-like product weighing 12.8 g. The product was 94% pure by GC-MS analysis, (66% yield) and was sometimes used, without further purification, in subsequent reactions. When desired, further purification (to 99.4%) was accomplished by column chromatography on Merck silica gel 60 (70-230 mesh) with 85:5:5:0.5 hexane/chloroform/ethyl acetate/methanol/aqueous ammonia.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[Cl:12]N1C(=O)CCC1=O>C(O)(C)C>[Cl:12][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[CH:10]=[CH:9][C:8]=1[NH2:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCCc1ccc(N)cc1
Solvent: CC(C)O
Product: COCCc1ccc(N)c(Cl)c1

Procedure:
2 g (13.2 mmol) of 4-(2-methoxy-ethyl)-phenylamine (Example 42b) and 1.85 g (13.9 mmol) of N-chlorosuccinimide (Aldrich, Buchs, Switzerland) in 26 ml of isopropanol are stirred at rt for 30 min. The reaction mixture is evaporated to dryness and the residue is taken in EtOAc. The organic layers is washed with sat. aqueous NaHCO3 (2×), dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography on silica gel (hexane-EtOAc 5:1 to 2:1) to provide the title compound as an oil. ES-MS: 186 (M+H)+; analytical HPLC: tret=2.42 minutes (Grad 1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:38]2[C:33]([CH:34]=[N:35][C:36](OS(C(F)(F)F)(=O)=O)=[N:37]2)=[CH:32][CH:31]=1.COCC(O)C.C(N(CC)C(C)C)(C)C.Cl>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[N:38]2[C:33]([CH:34]=[N:35][C:36]([NH:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:16]=3)=[N:37]2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)c2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(OC4CCNCC4)c3)nn12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(3-Amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (94 mg, 0.32 mmol), Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (100 mg, 0.3 mmol), 1-Methoxy-2-propanol (0.3 mL, 3 mmol), and N,N-Diisopropylethylamine (2 mL, 10 mmol) was heated and let stir overnight at 80° C. Concentrated added Hydrogen Chloride (2 mL, 60 mmol) and stir at room temperature for half and hour. The reaction was concentrated, dissolved in 2 mL DMSO, filtered and placed onto the Gilson. The pure fractions were frozen and lypholyzed over night to give [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[3-(piperidin-4-yloxy)-phenyl]-amine
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCCCO
Product: OCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 24 %

Procedure:
The procedure described in example 41 was followed but using 1,5-pentandiol (376 mg, 3.6 mmol) as alcohol instead of cis-2-buten-1,4-diol in the reaction with trityl chloride, which gave the title compound (300 mg, 24%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[CH:7]=[CH:8][CH2:9]Cl)([O-:3])=[O:2].[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:23]=2[N:24]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][N:20]([CH2:9][CH:8]=[CH:7][C:6]3[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:21][CH2:22][C:23]=2[N:24]=1
Reactant: O=[N+]([O-])c1cccc(C=CCCl)c1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc([N+](=O)[O-])c1)CC2
Yield: 56 %

Procedure:
Prepared from 3-nitro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform. Yield: 56% of theory, Melting point: 165°-168° C. (ether).
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C(N(CC)CC)C.[C:29](Cl)(=[O:38])[C:30]1[C:31]([O:36][CH3:37])=[CH:32][CH:33]=[CH:34][CH:35]=1.O>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]([NH:2][S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:7][CH:6]=1)(=[O:3])=[O:4])=[O:38]
Reactant: NS(=O)(=O)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: COc1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: COc1ccccc1C(=O)NS(=O)(=O)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Reaction time: 2 h

Procedure:
5 g (15 mmol) of N-(4-sulfamoylphenyl)-2,4-dichlorobenzamide are introduced into 80 ml of acetonitrile at 0° C., and 2.93 g (30 mmol) of triethylamine and a catalytic amount of DMAP (4-dimethylaminopyridine) are added. 2.47 g (15 mmol) of o-anisoyl chloride—dissolved in 20 ml of acetonitrile—are subsequently added dropwise. After a further 2 hours at room temperature, the mixture is transferred into water and the precipitate is filtered off with suction; Yield: 4.2 g (60%); M.p.: 140-146° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:13]([O:15][CH3:16])=[O:14].[F:22][N+]1C=C(C(F)(F)F)C=CC=1S([O-])(=O)=O.S([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:22])=[CH:5][C:4]=1[CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CCCCCC(CC(=O)OC)c1ccc(OC)cc1OC
Reactant: O=S(=O)([O-])c1ccc(C(F)(F)F)c[n+]1F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCCC(CC(=O)OC)c1cc(F)c(OC)cc1OC
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 18 %

Procedure:
A solution of 943 mg (3.20 mmol) of methyl 3-(2,4-dimethoxyphenyl)-octanoate [prepared as described in Preparation 32(i)] in 5 ml of 1,2-dichloroethane was added to a suspension of 864 mg (3.53 mmol) of 1-fluoro-5-trifluoromethylpyridinium-2-sulfonate in 10 ml of 1,2-dichloroethane, and the resulting mixture was stirred at 90° C. for 2.5 hours. The reaction mixture was then poured into a saturated aqueous solution of sodium sulfite, and the aqueous mixture was freed from the solvent by evaporation under reduced pressure, after which it was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 20 g of silica gel, using an 8:1 by volume mixture of hexane and ethyl acetate as the eluent, to give a mixture containing the title compound. This mixture was further purified by column chromatography through 40 g of silica gel, using a 7:1 by volume mixture of hexane and acetone as the eluent, to give the desired fluoride compound as an oily substance in a 18% yield.
Reaction SMILES: [OH-].[Na+].Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][S:11][C:12](=N)N)[CH:5]=1.BrC[CH2:17][CH2:18][Cl:19]>O>[Cl:19][CH2:18][CH2:17][CH2:12][S:11][CH2:10][C:6]1[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=1
Reactant: N=C(N)SCc1cccnc1
Reactant: ClCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSCc1cccnc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 59.6 %

Procedure:
A 10 N aqueous solution of sodium hydroxide (50 cc) is added, in the course of 10 minutes and whilst allowing the temperature to rise to 14° C. to a solution, cooled to 12° C. of 2-(pyrid-3-yl-methyl)isothiourea monohydrochloride (100 g) in distilled water (250 cc). After heating for 30 minutes at a temperature of 100° C. and then cooling to 12° C. a 10 N aqueous solution of sodium hydroxide (60 cc) is added dropwise and in the course of 10 minutes. 1-Bromo-3-chloropropane (82 g) is then added, whilst stirring, and stirring is continued for 20 hours at a temperature of about 20° C. The reaction mixture is then extracted three times with methylene chloride (430 cc in total). The organic extracts are combined and washed with distilled water (250 cc) and then dried over anhydrous magnesium sulphate. After filtration, the solution obtained is poured onto neutral silica gel (100 g) contained in a column of diameter 3 cm; the column is then eluted with methylene chloride (2300 cc). The first fraction (700 cc) is discarded; the second fraction (1600 cc) is collected and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. Pyrid-3-yl-methyl 3-chloropropyl sulphide (59 g) is thus obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[F:22][C:23]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[F:22][C:23]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:26]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)c1cccc(F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1cccc(F)c1F
Yield: 45.3 %

Procedure:
Preparation of example 97 from the title compound of Example 7 (hydrochloride) (40 mg, 0.128 mmol), 2,3-difluoro-benzoic acid (24 mg, 0.154 mmol), triethylamine (0.054 mL, 0.384 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (59 mg, 0.154 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 2:1 hexane:acetone increasing to 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (24 mg, 0.058 mmol) as a yellow powder in 45% yield.
Reaction SMILES: BrCCCCC[CH2:7][CH2:8][OH:9].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.[F:25][C:26]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=1OCCO>>[F:25][C:26]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=1[CH2:7][CH2:8][O:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: OCCCCCCCBr
Reactant: BrCCCCCCCOC1CCCCO1
Reactant: OCCOc1cccc(F)c1F
Product: Fc1cccc(CCOCCCCCCCOC2CCCCO2)c1F

Procedure:
The title compound, m/e=413.5 ([M−H]−), was produced in analogy with example 54, steps 1 to 6. Thus, 7-bromo-1-heptanol was protected in step 1, leading to 2-(7-bromo-heptyloxy)-tetrahydro-pyran, which was reacted in step 2 with 2-(2,3-difluorophenoxy)-ethanol, affording 2-(7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptyloxy)-tetrahydro-pyran, which after deprotection in step 3 gave 7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptan-1-ol. This was oxidized in step 4 to 7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptanoic acid, which was coupled in step 5 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride, leading to (R)-3-{7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptanoylamino}-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 6.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.O.[OH-].[Li+].C(OCC)(=O)C>CS(C)=O>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:4]2([O:17][CH:2]([CH2:18][OH:1])[CH2:3]2)[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC2CO2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(CO)O2
Temperature: 140 °C
Yield: 23.7 %

Procedure:
To a solution of 1.42 g of 4-(2,3-epoxypropan-1-yl)-1-(tert-butoxycarbonyl)piperidin-4-ol in dimethyl sulfoxide (20 ml) were added in a nitrogen atmosphere 5 ml of water and 2.32 g of lithium hydroxide and the resulting mixture was heated to 140° C. for 30 minutes. After adding ethyl acetate, the reaction mixture was washed with water thrice. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with dichloromethane/ethyl acetate) to thereby give 0.336 g of the title compound as colorless crystals.
Reaction SMILES: [NH4+:1].[Cl-].[N:3]#N.C[Al](C)C.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][C:18]([C:27](OCC)=O)=[N:17]2)=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.CO>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][C:18]([C:27]([NH2:3])=[NH:1])=[N:17]2)=[CH:12][CH:11]=1
Reactant: [NH4+]
Reactant: N#N
Reactant: CCOC(=O)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Product: N=C(N)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1

Procedure:
Part A: A stirred suspension of NH4Cl (2.68 g, 0.05 mol) in toluene (25 ml) is cooled to 0° C. in an N2 atmosphere. A solution of Me3Al in toluene (25 ml of a 2 M solution) is slowly added and the mixture is allowed to attain room temperature. A solution of ethyl 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate (3.29 gram, 10 mmol) in toluene (25 ml) is slowly added and the reaction mixture is stirred at 80° C. for 16 hours. After cooling to 0° C. methanol is slowly added and the formed precipitate is removed by filtration. The filtrate is concentrated and the residue is dissolved in a mixture of dichloromethane and methanol. The formed precipitate is removed by filtration. The filtrate is concentrated and the remaining residue crystallised from dichloromethane to give 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamidine.HCl (2.70 g, 73% yield). 1H-NMR (200 MHz, DMSO-d6): 3.08 (dd, J=18 and 7 Hz, 1H), 3.82 (dd, J=18 and 13 Hz, 1H), 5.84 (dd, J=13 and 7 Hz, 1H), 7.15-7.46 (m, 9H), 8.85 (br s, 2H), 9.00 (br s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]2[CH:41]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:43][C:39]=2[CH:38]=[N:37]1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:42]2[S:43][C:39]3[CH:38]=[N:37][N:36]([CH3:35])[C:40]=3[CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(cnn2C)s1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1ncc2sc(-c3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc21
Temperature: 90 °C

Procedure:
In a 30 mL sealed cap glass vessel, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (102 mg, 0.205 mmol), 1-methyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (175 mg, 0.410 mmol) and tetrakis(triphenylphosphine) palladium(0) (118 mg, 0.102 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. The reaction mixture was concentrated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the reaction mixture was stirred for 1 hour. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparative HPLC, eluting with a gradient of 15-65% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (75 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28-1.55 (m, 2H), 1.60 (d, J=14.15 Hz, 1H), 1.67-1.93 (m, 3H), 1.98 (dd, J=13.64, 4.29 Hz, 2H), 3.85 (br s, 1H), 3.99 (s, 2H), 4.24 (d, J=3.54 Hz, 1H), 4.38-4.54 (m, 2H), 7.14 (d, J=5.81 Hz, 1H), 7.62-7.88 (m, 3H), 8.62 (s, 1H), 9.27 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H21FN6OS, 401. found, 401.
Reaction SMILES: C(NC1C=CC(S(N)(=O)=O)=CC=1)(=O)C.C(Cl)(=O)CCCCC.Cl.C([NH:27][C:28]1[CH:44]=[CH:43][C:31]([S:32]([NH:35][C:36](=[O:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:34])=[O:33])=[CH:30][CH:29]=1)(=O)C>O.N1C=CC=CC=1>[C:36]([NH:35][S:32](=[O:33])([C:31]1[CH:30]=[CH:29][C:28]([NH2:27])=[CH:44][CH:43]=1)=[O:34])(=[O:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCC(=O)NS(=O)(=O)c1ccc(NC(C)=O)cc1
Agent: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Agent: CCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC(=O)NS(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
N1 -hexanoylsulfanilamide was prepared as follows. To a mixture of N4 -acetylsulfanilamide (55.0 g) and pyridine (54 mL) at 95° C. was added hexanoyl chloride (28.8 g) over a period of 20 min. After an additional hour the reaction mixture was cooled to room temperature and the reaction was worked up by diluting with 600 mL D.I. water and acidifying with aqueous HCl. The product of this reaction, N4 -acetyl-N1 -hexanoylsulfanilamide, was isolated by filtration and washed with D.I. water (700 mL) to afford an off-white solid. This material was carried directly to the next step.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([CH3:25])=[N:7][C:8]2[N:9]([CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[N+:2]=[N-:3].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C1COCC1>[N:1]([CH2:4][C:5]1[C:6]([CH3:25])=[N:7][C:8]2[N:9]([CH:19]=[C:20]([C:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:24])[N:21]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[N+:2]=[N-:3]
Reactant: Cc1nc2nc(C(=O)O)cn2c(-c2ccc(Cl)cc2Cl)c1CN=[N+]=[N-]
Reactant: C1COCCN1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1nc2nc(C(=O)N3CCOCC3)cn2c(-c2ccc(Cl)cc2Cl)c1CN=[N+]=[N-]
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a stirred solution of (+)-6-(azidomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylic acid (150 mg, 0.40 mmol) in THF (10 mL) was added morpholine (52 mg, 0.60 mmol), HOAt (81 mg, 0.60 mmol), EDC (114 mg, 0.60 mmol) and iPr2NEt (103 mg, 0.80 mmol). The reaction was kept at room temperature for 2 h and was concentrated under reduced pressure. The residue was diluted with EtOAc and the organic layer was washed with 1N HCl, 1N NaOH and brine prior to drying over anhydrous MgSO4. Filtration and concentration under reduced pressure afforded (+)-(6-(azidomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-2-yl)(morpholino)methanone (177 mg, 100% crude yield) as a clear glass.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O(C(C)(C)C)[K]>C1(C)C=CC=CC=1.C(OCC)C.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Clc1ccccn1
Agent: CC(C)(C)O[K]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccccn2)cc1
Temperature: 25 °C

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 33 mg (0.046 mmol) of [(t-Bu)2P(Cl)PdCl2]2, 0.50 g (4.4 mmol) of 2-chloropyridine, 0.70 g (4.14 mmol) of Ph2NH and 0.58 g (5.17 mmol) of KO-t-Bu in 2 mL of toluene. The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 100 mL of diethyl ether and 20 mL of H2O. The layers were separated, and organic layer was washed with H2O (2×50 mL), brine (30 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 2-pyridyldiphenylamine. LC-MS Found: 247.3 (M++1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1
Reactant: CN1CCC[C@H]1CO
Reactant: Clc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1cnccn1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
(S)-(-)-1-Methyl-2-pyrrolidinemethanol (Aldrich Chemical Co., 0.5 g, 4.34 mmol) was dissolved in anhydrous THF and brought to 0° C. NaH ((80% dispersion in mineral oil), 131 g, 4.56 mmol) was added and the reaction mixture was allowed to warm to room temperature with stirring. After 30 minutes 2-chloropyrazine (0.497 g, 4.34 mmol) was added via syringe. The mixture was stirred for 48 hours. The solvent was then evaporated in vacuo and the mixture diluted with chloroform, washed with saturated NaHCO3 and a brine solution. The organic layer was then dried over MgSO4. The resulting crude material was purified by flash chromatography (10% MeOH/CHCl3) to give 0.81 g (97% yield) of the title compound as an oil. TLC Rf =0.3 (10% MeOH/CHCl3). MS (DCI/NH3) m/e 194 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.24 (d, J=1.5 Hz, 1H, 8.11 (d, J=3 Hz, 1H), 8.07 (dd, J=3, 1.5 Hz, 1H), 4.36 (dd, J=9, 6 Hz, 1H), 4.28 (dd, J=9, 6 Hz, 1H), 3.16-3.08 (m, 1H, 2.7-2.58 (m, 1H, 2.47 (s, 3H), 2.34-2.24 (m, 1H, 2.08-1.93 (m, 1H, 1.91-1.67 (m, 3H).