Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]2[CH:14]=[C:15]([C:26]([O:28][CH3:29])=[O:27])[CH:16]=[C:17]([O:18]CC3C=CC=CC=3)[C:4]=2[N:3]=1>O1CCCC1.[OH-].[Pd+2].[OH-]>[OH:18][C:17]1[C:4]2[N:3]=[C:2]([CH3:1])[N:6]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[C:5]=2[CH:14]=[C:15]([C:26]([O:28][CH3:29])=[O:27])[CH:16]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c2nc(C)n(C(=O)OC(C)(C)C)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(O)c2nc(C)n(C(=O)OC(C)(C)C)c2c1
Reaction time: 2 h
Yield: 32.3 %

Procedure:
A mixture of 1-(1,1-dimethylethyl) 6-methyl 2-methyl-4-[(phenylmethyl)oxy]-1H-benzimidazole-1,6-dicarboxylate (12.1 g, crude, STEP 2) and 20% palladium hydroxide (6.0 g) in tetrahydrofuran (250 mL) was stirred under hydrogen gas for 2 hours. The resulted mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuum. The residue was washed with hexane/diethyl ether (10:1) to give the title compound as a white solid (3.02 g, 28% for 3 steps).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.Cl.[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[NH:31])[NH2:30])[CH2:24]1.CC(C)([O-])C.[K+]>C(O)C>[CH3:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[C:5]1[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[CH:3][N:30]=[C:29]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([CH3:22])[CH2:24]2)[N:31]=1
Reactant: CC1CCCN(C(=N)N)C1
Reactant: Cc1cc(C(=CN(C)C)C(=O)c2ccoc2C)ccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1cc(-c2cnc(N3CCCC(C)C3)nc2-c2ccoc2C)ccn1
Temperature: 25 °C
Yield: 66 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-f uranyl)-2-(2-methyl-4-pyridinyl)-2-propen-1-one (541 mg, 2.000 mmol) and 3-methyl-1-piperidinecarboximidamide hydrochloride (533 mg, 3 mmol) in ethanol (10 ml) was stirred at room temperature. Potassium tert-butoxide (449 mg, 4.00 mmol) was added and the mixture was heated at reflux for 90 minutes. After cooling to room temperature the solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate in isohexane to give 4-(2-methyl-3-furanyl)-2-(3-methyl-1-piperidinyl)-5-(2-methyl-4-pyridinyl)pyrimidine as a gum (460 mg, 66%). A solution of 4-(2-methyl-3-furanyl)-2-(3-methyl-1-piperidinyl)-5-(2-methyl-4-pyridinyl)pyrimidine (460 mg, 1.3 mmol) in dichloromethane (2 ml) was treated with hydrogen chloride (1M in diethyl ether, 1.5 ml). The solvent was evaporated and the residue was co-evaporated with diethyl ether (×2). The residue was triturated with diethyl ether and the resulting solid was collected, washed with diethyl ether and dried to give the title compound as a pale yellow solid (450 mg, 89%). LC/MS [M+H]+=349. 1H NMR (400 MHz, d6-DMSO): δ 8.59 (1H, d), 8.54 (1H, s), 7.81 (1H, s), 7.57-7.52 (1H, m), 7.51 (1H, d), 6.02 (1H, d), 4.70-4.60 (2H, m), 3.06-2.98 (1H, m), 2.70-2.77 (1H, m), 2.66 (3H, s), 2.39 (3H, s), 1.84-1.19 (5H, m), 0.93 (3H, d).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24](OC)=[O:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[CH2:24][OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1nn(C2CCCCO2)c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(CO)nn2C1CCCCO1
Temperature: -70 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a stirred mixture of LiAH4 (390 mg, 11.50 mmol, 1.00 equiv) in anhydrous THF (100 mL) maintained under nitrogen at −70° C. was added dropwise a solution of (R/S) methyl 5-(tert-butyldimethylsilyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (1.33 g, 3.41 mmol, 1.00 equiv) in THF. The reaction was stirred at −40° C. for 1 h and then quenched by the addition of 20 mL of saturated NH4Cl solution. The resulting mixture was concentrated under vacuum to remove the excess THF. The mixture was extracted with 3×50 mL of dichloromethane. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to afford 1 g (81%) of (R/S) (5-(tert-butyldimethylsilyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methanol as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.22 (d, J=9.0 Hz, 1H), 6.95 (d, J=2.1 Hz, 1H), 6.80 (dd, J=8.7 Hz, 2.1 Hz, 1H), 5.44-5.40 (m, 1H), 4.80 (s, 2H), 3.80-3.71 (m, 2H), 2.01-1.75 (m, 2H), 1.69-1.25 (m, 4H), 0.80 (s, 9H), 0.10 (s, 6H) ppm. LCMS (method A, ESI): RT=1.71 min, m/z=363.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([N:14]([CH3:16])[CH3:15])=[N:10][N+:11]([O-:13])=[O:12])=[CH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].CC#N.[CH:26]1[CH:31]=[CH:30][C:29]([O:32][C:33](Cl)=[S:34])=[CH:28][CH:27]=1>O>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:33]([O:32][C:29]2[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=2)=[S:34])[C:9]([N:14]([CH3:16])[CH3:15])=[N:10][N+:11]([O-:13])=[O:12])=[CH:5][N:6]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(C)C(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(=S)Oc1ccccc1
Yield: 75.8 %

Procedure:
To a mixture of 1-(2-chloro-5-thiazolylmethyl)-3,3-dimethyl-2-nitroguanidine (200 mg), K2CO3 (420 mg) and CH3CN (13 ml) was added phenyl chlorothionoformate (260 mg) dropwise in 3 minutes at 3° C. under stirring. After stirring at room temperature for 4 hours, water (10 ml) was added to the mixture which was extracted with CHCl3 (20 ml). The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was crystallized from AcOEt-Et2O to afford 230 mg of 1-(2-chloro-5-thiazolylmethyl)-3,3-dimethyl-2-nitro-1-phenoxythiocarbonylguanidine (Compound No. 44) as a white crystal, m.p. 161°-162° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:14][CH:15]=2)=[O:9])[CH:7]=1.C([Sn](CCCC)(CCCC)C1C=CC=CN=1)CCC>C1(C)C(C)=CC=CC=1.CC(OC)(C)C.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>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([CH:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:14][CH:15]=2)[OH:9])[CH:7]=1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1C
Product: COc1ccc(Br)cc1C(O)c1ccc(Nc2ccc(F)cc2F)nc1
Yield: 39.6 %

Procedure:
(5-Bromo-2-methoxy-phenyl)-[6-(2,4-difluoro-phenylamino)-pyridin-3-yl]-methanone (50 mg; 0.12 mmol), 2-tributylstannylpyridine (88 mg; 0.26 mmol) and PdCl2(PPh3)2 (25 mg; 0.035 mmol) are dissolved in xylene (2 ml) and refluxed for 4.5 hours. The reaction mixture is diluted with TBME and filtered through a bed of SiO2. The resulting solid is dissolved in ether, crystallized by adding hexanes and yields the title compound as yellowish crystals (20 mg; 40%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:12]=2)=[O:9])=[C:6]([Cl:26])[CH:5]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](O)=[O:34]>>[Cl:26][C:6]1[CH:5]=[C:4]([CH:25]=[CH:24][C:7]=1[C:8](=[O:9])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)[CH2:3][NH:2][C:33](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=1
Reactant: O=C(O)c1ccccn1
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Agent: Cl
Product: O=C(NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1)c1ccccn1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((tert-butoxycarbonylamino)methyl)-2-chlorobenzoic acid via Procedure G to yield tert-butyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate. Tert-butyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate was subsequently treated with 4N HCl in Dioxane to remove the Boc protecting group and form the HCl salt of 4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 54 mg of the crude HCl salt of 4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to picolinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide. MS (Q1) 477.3 (M)+.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([NH:30][CH:31]=[O:32])[CH:29]=1)[NH:26][C:25](=[O:33])[CH2:24]2>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13](/[CH:16]=[C:24]3\[C:25](=[O:33])[NH:26][C:27]4[C:23]\3=[CH:22][C:21]([F:20])=[CH:29][C:28]=4[NH:30][CH:31]=[O:32])=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Reactant: O=CNc1cc(F)cc2c1NC(=O)C2
Product: Cc1c(/C=C2\C(=O)Nc3c(NC=O)cc(F)cc32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 79 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-formamide 20c obtained from step 3 of Example 20 as starting materials to obtain (Z)—N-{3-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl}-formamide 26 (71 mg, yield 79%) as a red solid.
Reaction SMILES: [Br:1][CH2:2][C:3](C1C=CC(NS(C2C=CC(C)=CC=2)(=O)=O)=CC=1)=[O:4].C([C:25]1[CH:41]=[CH:40][C:28]([NH:29][S:30]([C:33]2C=CC(C)=CC=2)(=[O:32])=[O:31])=[CH:27][CH:26]=1)(=O)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCOCC>[Br:1][CH2:2][C:3]([C:27]1[CH:26]=[CH:25][CH:41]=[CH:40][C:28]=1[NH:29][S:30]([CH3:33])(=[O:31])=[O:32])=[O:4]
Reactant: CC(=O)c1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)CBr)cc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CS(=O)(=O)Nc1ccccc1C(=O)CBr

Procedure:
In a similar manner 4'-(2-bromoacetyl)-p-toluenesulfonanilide, (m.p. 174°-1765° with decomposition,) can be prepared by bromination of 4'-acetyl-p-toluenesulfonanilide (Preparation 1) [See R. H. Vloth, et al., J. Med. Chem. 9, 88 (1966)]. For this preparation anhydrous ether can also be used as solvent; benzoyl peroxide can be used as a catalyst. The product is crystallized from acetonitrile.
Reaction SMILES: CC[O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8][N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5].O.[OH-].[Li+]>CO.O>[C:16]([O:15][C:13]([N:7]1[CH2:8][CH:9]([CH3:12])[CH2:10][CH2:11][C@H:6]1[C:4]([OH:5])=[O:3])=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)[C@@H]1CCC(C)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CC[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-5-methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (1.4 g, 5.16 mmol) in methanol (15 mL) and water (5 mL) was added lithium hydroxide monohydrate (650 mg, 15.48 mmol). The reaction mixture was stirred at RT overnight and concentrated to give the residue, which was extracted with EtOAc/water. The aqueous layer was acidified with 1 N HCl, and extracted with EtOAc to give the organic layer, which was dried and concentrated to give the crude product.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12]CCCCCCO>C1(C)C=CC=CC=1>[C:1]1(=[O:6])[NH:12][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: NCCCCCCO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2ccccc21

Procedure:
A solution of phthalic anhydride (32.0 g, 0.21 mol) and 6-aminohexanol (25.0 g, 0.21 mol) in 180 mL dry toluene was heated to reflux for 3 hrs. When the intermediate phthalimide was formed, PBr3 (18.2 mL, 0.58 mol in 20 mL toluene) was added dropwise and the reaction was stirred at 100° C. for 1.5 hrs. The reaction mixture was filtered thru a microfiber filter and the filtrate was concentrated in vacuo to give the crude product which then crystallized from toluene to give 6-phthalimido-1-bromohexane. (86% yield).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([CH:17]=[N:18]O)=[C:4]2[CH2:3]1>C(OC(=O)C)(=O)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]#[N:18])=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C=NO)ncn2-c2ccccc2C1=O
Solvent: CC(=O)OC(C)=O
Product: CN1Cc2c(C#N)ncn2-c2ccccc2C1=O

Procedure:
A solution of 4.8 g (18.7 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde-3-oxime in 50 ml of acetic acid anhydride is heated to boiling under reflux for 28 hours. After evaporation of the mixture in vacuo, the residue is taken up in 150 ml of chloroform and washed twice with 30 ml of saturated sodium hydrogen carbonate solution each time and with 30 ml of water. The organic phase is dried over magnesium sulphate and evaporated. After column chromatography on silica gel and recrystallisation from ethyl acetate, there is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile of melting point 184°-186° C.
Reaction SMILES: CCCCCC.[Li]CCCC.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.[I:21]I>C1COCC1>[Cl:12][C:13]1[CH:20]=[C:19]([I:21])[C:16]([C:17]#[N:18])=[CH:15][N:14]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1cnc(Cl)cc1I
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
To a mixture of THF (100 mL) and hexane (40 mL) under nitrogen atmosphere was added DIPA (22.21 mL, 158.78 mmole, 1.1 eq). The mixture was cooled to −80° C. and to this was added n-BuLi (63.57 mL, 158.78 mmole, 1.1 eq) dropwise. After completion of addition the resulting mixture was allowed to warm and stirred at −10° C. for 15 min. The reaction mixture was again cooled to −80° C. and a solution of 6-chloro-nicotinonitrile (20 g, 144.35 mmol, 1 eq) in THF (100 mL) was added dropwise. The resulting mixture was stirred at −80° C. for 1 h. After 1 h a solution of iodine (43.96 g, 173.22 mmole, 1.2 eq) in THF (100 mL) was added in one portion. After completion of the reaction, the reaction was quenched with water (100 mL) and extracted with diethyl ether (6×100 mL). Combined organic layers were washed with saturated solution of sodium thiosulfate (2×100 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give crude product. Crude compound was purified by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate-hexane as the eluant to yield the title compound as a faintly yellow solid (15 g, 39%). 1H-NMR (400 MHz, DMSO-d6): δ 8.38 (s, 1H), 8.79 (s, 1H). LC-MS calculated for C6H2ClIN2 (M+H) 264.90. found 264.9.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[ClH:11].[CH3:12][OH:13]>>[ClH:11].[CH3:12][O:13][C:1](=[NH:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: CO
Reactant: COc1ccc(C#N)cc1
Agent: Cl
Product: COC(=N)c1ccc(OC)cc1
Temperature: 0 °C

Procedure:
25 g of anisonitril was dissolved in 250 ml of methanol. After saturation with hydrogen chloride gas under cooling in ice-water and stirring, the solution was stirred at room temperature for 15 hours. Then, methanol was evaporated in vacuo. Ether was added to the residue and the crystals were filtered off and dried. Whereby 35.9 g of the desired substance was obtained as white crystals. Melting point is 111° to 112° C. (Decomposition).
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C@@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][C:27]2=[CH:29][N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=32)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:5][C:6]([OH:8])=O.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:33]([O:40][NH:41][C:6](=[O:8])[CH2:5][C@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][C:27]2=[CH:29][N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=32)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:3][CH:2]([CH3:32])[CH3:1])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](CC(=O)NOCc1ccccc1)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Alternatively, to a solution of (3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid (2.5 g, 5.82 mmol), HOBtH2O(0.89 g, 1 eq.) and O-benzyl hydroxylamine (2.2 mL, 3 eq.) in DMF (200 mL) at 0° C. was added EDCI (2.77 g, 2.5 eq.). The resulting mixture was then stirred overnight. DHF was removed by pump distillation at 65° C. To the residue was then added methanol (14 mL) followed by ether (140 mL). With stirring at 0° C., 0.5 N HCl (140 mL) was added, followed by petroleum ether (140 mL). The mixture was stirred at 0° C. for 15 minutes, then the white solid was suction filtered and subsequently washed with water (100 mL) followed by 1:1 ether/petroleum ether (100 mL). Drying under vacuum (P2O5) for 3 hours gave (3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0 13,18 ]-nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide as a white solid (2.7 g, 84.9%).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)=[O:3].[F:12][C:13]1[CH:14]=[C:15]([C:20]2([O:30][CH3:31])[CH2:24][CH2:23][N:22]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:21]2)[CH:16]=[C:17](F)[CH:18]=1>>[C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:17]2[CH:16]=[C:15]([C:20]3([O:30][CH3:31])[CH2:24][CH2:23][N:22]([CH2:25][C:26]([F:27])([F:28])[F:29])[CH2:21]3)[CH:14]=[C:13]([F:12])[CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: COC1(c2cc(F)cc(F)c2)CCN(CC(F)(F)F)C1
Product: COC1(c2cc(F)cc(Sc3ccc(NC(C)=O)cc3)c2)CCN(CC(F)(F)F)C1
Yield: 54 %

Procedure:
Using an analogous procedure to that described in Example 6, 4-mercaptoacetanilide was reacted with 3-(3,5-difluorophenyl)-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine to give 3-[3-(4-acetamidophenylthio)-5-fluorophenyl]-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine in 54% yield, m.p. 127°-129° C.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:15]=[C:14]([C:16]3[N:17]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=4[F:37])[C:18](=[O:28])[C:19]([C:26]#[N:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=3)[S:13][CH:12]=2)[CH:6]=1.C1COCC1.O[Li].O.Cl>O>[C:26]([C:19]1[C:18](=[O:28])[N:17]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[C:16]([C:14]2[S:13][CH:12]=[C:11]([C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:38])=[O:2])[CH:10]=[CH:9][CH:8]=3)[CH:15]=2)=[CH:21][C:20]=1[C:22]([F:24])([F:25])[F:23])#[N:27]
Reactant: COC(=O)Cc1cccc(-c2csc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)c2)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(C(F)(F)F)cc(-c2cc(-c3cccc(CC(=O)O)c3)cs2)n(Cc2ccc(F)cc2F)c1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
(3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-acetic acid methyl ester (0.988 g, 1.81 mmoles) was dissolved into THF (20 mL) and water (6 mL). To this homogeneous mixture was then added LiOH hydrate (152 mg, 3.62 mmoles). This mix was then stirred at 30° C. for 2 hours. After this period the reaction mixture was acidified to pH˜3 using 1H HCl and was evaporated in vacuo. The resulting residue was extracted with DCM (3×15 mL) and the resulting organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to yield crude product. The crude product was purified using flash silica chromatography (0-5% MeOH/DCM) to yield (3-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-acetic acid (625 mg, 65%) as a yellow solid. 1H-NMR (CDCl3): δ 7.64 (br d, J=1.5 Hz, 1H), 7.41-7.38 (m, 2H), 7.32-7.30 (m, 1H), 7.13-7.06 (m, 1H), 6.90-6.84 (m, 1H), 6.82-6.75 (m, 1H), 6.64 (s, 1H), 5.43 (s, 2H), 3.70 (s, 2H). MS(ES+): 531.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=3)[N:22]=2)[CH2:11][CH2:10]1
Reactant: Clc1ccccc1CN1CCCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCCN(Cc4ccccc4Cl)CC3)nn12

Procedure:
A mixture of 1-[(2-chlorophenyl)methyl]-1,4-diazepane and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-chlorophenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:4]=1)#[N:2].C(N(CC)CC)C.CO.[H][H]>[Pd].C1(C)C=CC=CC=1.CCOC(C)=O>[NH2:2][CH2:1][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:4]=1
Reactant: Cc1nc(C#N)cc(Oc2ccc(CS(=O)(=O)N(C)C(=O)OC(C)(C)C)cc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1nc(CN)cc(Oc2ccc(CS(=O)(=O)N(C)C(=O)OC(C)(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 140.5 %

Procedure:
Combine tert-butyl N-[[4-(6-cyano-2-methyl-pyrimidin-4-y)oxyphenyl]methylsulfonyl]-N-methyl-carbamate (400 mg, 0.96 mmol), triethylamine (290 mg, 2.9 mmol), MeOH (20 mL), and EtOAc (20 mL) in a PARR reactor. Add 5% palladium on carbon (203 mg, 0.096 mmol). Seal the PARR reactor and pressurize it with hydrogen (345 kPa). Shake the reactor at ambient temperature for 17 hours. Depressurize and open the reactor. Add an additional amount of 5% palladium on carbon (200 mg, 0.094 mmol); re-pressurize the reactor with hydrogen (414 kPa) and shake the reactor for an addition 17 hours while maintaining it at ambient temperature. Depressurize and open the reactor. Filter the contents through diatomaceous earth, and concentrate the filtrate under reduced pressure to provide a residue. To purify, add toluene and concentrate under reduced pressure to provide an orange-red residue. Repeat the toluene addition and removal 3 times to provide the title compound as a pink solid (0.57 g, 98.8%, 70% pure). MS (m/z): 423 (M+1).