Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[CH:7][C:6]([C:13]#[N:14])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1.Br[CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>C(OCCO)C>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[NH:15][C:5]1[C:4]2[CH:3]=[C:2]3[NH:1][CH2:25][CH2:26][O:12][C:11]3=[CH:10][C:9]=2[N:8]=[CH:7][C:6]=1[C:13]#[N:14]
Reactant: N#Cc1cnc2cc(O)c(N)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCCO
Product: N#Cc1cnc2cc3c(cc2c1Nc1ccc(F)c(Cl)c1)NCCO3
Temperature: 135 °C
Yield: 45.1 %

Procedure:
An amount of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-hydroxy-quinoline-3-carbonitrile (4 g, 12.2 mmol) was stirred in 2-ethoxyethanol (480 mL), and to this were added 1,2-dibromoethane (22.9 g, 12.2 mmol), and potassium carbonate (10.1 g, 73 mmol), and the mixture was heated at 135° C. for 0.5 hours. After cooling to room temperature, the mixture was filtered over a thin silica pad and evaporated to an oil. To this was added ethyl acetate and saturated brine solution, and the layers were separated. The organic layer was dried on sodium sulfate and evaporated to a brown oil. Purification was carried out by flash chromatography (70% ethyl acetate in hexane) to yield a yellow solid (1.95 g, 45% yield), m.p. 244-245° C.; 1H NMR (DMSO-d6) δ 9.32 (s, 1H), 8.29 (s, 1H), 7.36 (m, 2H), 7.19 (s, 1H), 7.12 (m, 2H), 6.59 (s, 1H), 4.27 (m, 2H), 3.37 (m, 2H); HRMS (EI) m/z 355.07512 (M+1). Analysis for C18H12ClFN4.O0.1H2O.0.4CH3CO2C2H5: Found: C, 59.59; H, 3.66; N, 14.69. Calcd: C, 59.97; H, 3.93; N, 14.29.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:13]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([CH3:13])[CH:9]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: COc1cc(C=O)c(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(C=O)c(C)cc1Cl
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a degassed solution of 2-bromo-4-chloro-5-methoxybenzaldehyde (1.46 g, 5.9 mmol) and trimethylboroxine (0.82 mL, 5.9 mmol) in 1,4-dioxane (80 mL) was added potassium carbonate (2.43 g, 17.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.68 g, 0.6 mmol). The mixture was heated under reflux for about 23 h, then more tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) and trimethylboroxine (0.2 mL, 1.4 mmol) were added and the mixture was heated under reflux for about another 8 h. After cooling to rt the mixture was filtered over diatomaceous earth and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:6) to give 4-chloro-5-methoxy-2-methylbenzaldehyde (0.87 g, 4.7 mmol, 81%) as a pale yellow solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.60 (3 H, s); 3.95 (3 H, s); 7.29 (1 H, s); 7.37 (1 H, s); 10.3 (1 H, s).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([SH:11])[CH:7]=[CH:8]2)=[CH:3][CH:2]=1.Br[CH2:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]>>[CH:5]1[C:4]2[C:9](=[CH:10][CH:1]=[CH:2][CH:3]=2)[CH:8]=[CH:7][C:6]=1[S:11][CH2:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]
Reactant: Sc1ccc2ccccc2c1
Reactant: CC(C)=CCCC(C)=CCBr
Product: CC(C)=CCCC(C)=CCSc1ccc2ccccc2c1

Procedure:
2-thionaphthol is reacted with 1-bromo-3,7-dimethyl-octa-2,6-diene to produce 3,7-dimethyl-octa-2,6-dienyl 2-naphthyl sulphide (boiling point = 138° C/0.25 mmHg;
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:10]([NH:17][C:18](=[O:28])[CH2:19][CH:20]([C:24]([F:27])([F:26])[F:25])[CH2:21][CH2:22]Cl)=[C:9]([F:29])[CH:8]=1.[OH-].[Na+]>O>[Cl:6][C:7]1[C:12]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:10]([N:17]2[CH2:22][CH2:21][CH:20]([C:24]([F:27])([F:26])[F:25])[CH2:19][C:18]2=[O:28])=[C:9]([F:29])[CH:8]=1
Reactant: CC(C)Oc1cc(NC(=O)CC(CCCl)C(F)(F)F)c(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cc(N2CCC(C(F)(F)F)CC2=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 6 h
Yield: 63.6 %

Procedure:
To a tetrahydrofuran (16 ml) solution of 1.4 g (3.6 mmol) of N-(4'-chloro-2'-fluoro-5'-isopropyloxyphenyl )-5-chloro-3-(trifluoromethyl)pentanamide were added 16 ml water and 2 ml 50% NaOH (aq). The mixture was heated to 50° C. while stirring vigorously. After 6 hours the reaction was allowed to cool to room temperature, stirring was stopped and the aqueous layer was removed. The organic layer was evaporated in vacuo, then the residue was taken up in ether (50 ml), washed with water (2×50 ml) and then brine. The original aqueous layer was extracted with a second 50 ml portion of ether, the combined organic layers were washed with brine (50 ml) and dried (MgSO4). The solvent was removed in vacuo to yield 1.3 g. of a brown solid which was recrystallized from hexanes to yield 0.81 g (64% yield) of a brown solid (m.p. 98°-102° C.).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]2[N:7]=[CH:8][N:9]([C:32]=2[N:33]=[C:34]([NH2:36])[N:35]=1)[C@@H:10]1[O:31][C@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@@H:12]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:11]1)[CH:2]=[CH2:3].[Si]([N:41]=[N+:42]=[N-])(C)(C)C>>[CH2:1]([O:4][C:5]1[C:6]2[N:7]=[CH:8][N:9]([C:32]=2[N:33]=[C:34]([N:36]=[N+:41]=[N-:42])[N:35]=1)[C@@H:10]1[O:31][C@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:26])[CH3:25])[C@@H:12]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:11]1)[CH:2]=[CH2:3]
Reactant: C=CCOc1nc(N)nc2c1ncn2[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: C=CCOc1nc(N=[N+]=[N-])nc2c1ncn2[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Yield: 63 %

Procedure:
As described for the synthesis of 2a, this compound was prepared by a reaction 1b (3.0 g, 5.6 mmol) with TMS—N3 (10 molar equiv) and t-BuONO (10 molar equiv). Chromatographic purification of the crude material on a silica gel column using 20% EtOAc in hexanes afforded 1.98 g (63% yield) of 2b as a viscous, yellow oil. Rf(SiO2/30% EtOAc in hexanes)=0.63. IR (neat): 2956, 2930, 2857, 2130, 1600 cm−1. 1H NMR (CDCl3): δ 8.18 (s, 1H, Ar—H), 6.42 (t, 1H, H-1′, J=6.4 Hz), 6.18-6.11 (m, 1H, ═CH), 5.49 (dd, 1H, ═CHtrans, J=1.4, 17.2 Hz), 5.33 (dd, 1H, ═CHcis, J=1.4, 10.2 Hz), 5.11 (d, 2H, OCH2, J=5.8 Hz), 4.61-4.59 (m, 1H, H-3′), 4.01 (app q, 1H, H-4′, Japp˜3.4 Hz), 3.88 (dd, 1H, H-5′, J=4.0, 10.2 Hz), 3.79 (dd, 1H, H-5′, J=3.0, 10.2 Hz), 2.56 (app quint, 1H, H-2′, Japp˜6.5 Hz), 2.43 (ddd, 1H, H-2′, J=3.9, 5.9, 10.3 Hz), 0.93 and 0.92 (2s, 18H, t-Bu), 0.11 (s, 12H, SiCH3). Resonances of the tetrazolyl form (<5%): δ 8.25 (s, 1H, Ar—H), 4.64-4.63 (m, 1H, H-3′), 2.64-2.62 (m, 1H, H-2′). 13C NMR (CDCl3): δ 161.0, 155.8, 153.0, 140.6, 132.1, 119.3, 88.1, 84.5, 71.9, 68.6, 68.2, 62.9, 41.6, 26.1, 25.9, 18.5, 18.1, −4.4, −4.6, −5.3. 1H NMR (DMSO-d6): δ 8.47 (s, 1H, Ar—H), 6.32 (t, 1H, H-1′, J=6.4 Hz), 6.16-6.09 (m, 1H, ═CH), 5.46 (d, 1H, ═CHtrans, J=18.0 Hz), 5.33 (d, 1H, ═CHcis, J=10.7 Hz), 5.07 (d, 2H, OCH2, J=5.4 Hz), 4.62 (m, 1H, H-3′), 3.58 (d, 1H, H-4′, J=4.0 Hz), 3.78 (dd, 1H, H-5′, J=5.9, 11.2 Hz), 3.67 (dd, 1H, H-5′, J=4.4, 11.2 Hz), 2.90 (app quint, 1H, H-2′, Japp˜6.5 Hz), 2.34 (dd, 1H, H-2′, J=5.2, 11.2 Hz), 0.93 and 0.83 (2s, 18H, t-Bu), 0.12, 0.01, and 0.0.1 (3s, 12H, SiCH3). Resonances of the tetrazolyl form (<10%): δ 8.57 (s, 1H, Ar—H), 4.70 (m, 1H, H-3′), 0.81 (s, 18H, t-Bu), 0.13, 0.04, and −0.03 (3s, 12H, SiCH3). HRMS calculated for C25H43N7O4Si2Na [M+Na]+: 584.2807 found: 584.2818.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[CH:4]=1.[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[CH3:13][O:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])[CH2:2][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1)OCC
Temperature: 100 °C

Procedure:
In a sealed tube, a mixture of 4-(bromomethyl)-2-methoxy-1-nitrobenzene (4.22 g, 17.2 mmol) and triethyl phosphite (3.5 g, 21 mmol) was heated to 100° C. for 16 h. The reaction was cooled to ambient temperature, transferred to a round bottom flask, and concentrated in vacuo. The crude oil was adsorbed onto a pre-filled solid loading cartridge [RediSepRf 25 gram] and purified using the Teledyne/ISCO system [RediSepRf Silica 40 gram], eluting with 0-5% MeOH:CH2Cl2. The desired fractions were combined and concentrated in vacuo, affording the title material as a yellow oil, 5.0439 g (87%, 14.970 mmol). 1H NMR (CDCl3) δ ppm 7.83 (dd, J=8.2, 0.9 Hz, 1H), 7.08 (t, J=1.9 Hz, 1H), 6.94 (dt, J=8.3, 2.0 Hz, 1H), 4.07 (ddd, J=8.3, 7.1, 1.3 Hz, 4H), 3.97 (s, 3H), 3.14-3.25 (m, 2H), 1.29 (t, J=7.1 Hz, 6H). MS (ES+): m/z 304.00 (100) [MH+]. HPLC: tR=2.89 min (ZQ3, polar—5 min).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@@H:7]2[NH:10]C(=O)OCC2C=CC=CC=2)[O:3]1>C(OCC)(=O)C.[Pd]>[NH2:10][C@H:7]1[CH2:6][CH2:5][C@@H:4]2[CH2:9][C@H:8]1[C:2](=[O:1])[O:3]2
Reactant: O=C(N[C@H]1CC[C@@H]2C[C@H]1C(=O)O2)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@@H]2C[C@H]1C(=O)O2
Yield: 99.5 %

Procedure:
A solution of benzyl (1R,2S,5R)-7-oxo-6-oxa-bicyclo[3.2.1]octan-2-ylcarbamate (20 g, 72.6 mmol) in ethyl acetate (125 mL) was treated with 1.3 g of 10%Pd/C and hydrogenated overnight at 55 psi of H2 in a Parr shaker overnight. The catalyst was filtered and the filtrate concentrated in vacuo to give 10.2 g (100%) of (1R,2S,5R)-2-amino-6-oxa-bicyclo[3.2.1]octan-7-one as an oil. This was used without further purification. MS found: (M+H)+=142.06.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:21]([O:23][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)[CH3:22].CCN(C(C)C)C(C)C>CC#N>[CH2:21]([O:23][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:9]1[C@H:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:22]
Reactant: CCOC(=O)CCCCCBr
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCN1[C@@H](c2ncccc2C)CCC[C@H]1c1ncccc1C
Reaction time: 23 h
Yield: 90.2 %

Procedure:
A solution of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (308 mg, 1.15 mmol), 6-bromo-hexanoic acid ethyl ester (283 mg, 1.27 mmol), DIPEA (260 μL, 1.49 mmol) and KI (10 mg, 0.060 mmol) in CH3CN (12 mL) was warmed to 60° C. and stirred for 23 h according to General Procedure A. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (94:5:1) afforded 6-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-hexanoic acid ethyl ester (425 mg, 90%) as a yellow oil. 1H NMR (CDCl3) δ 0.60-0.68 (m, 2H), 0.79-0.85 (m, 1H), 1.13-1.25 (m, 5H), 1.58-1.70 (m, 3H), 1.94-1.98 (m, 4H), 2.08-2.25 (m, 7H), 2.48 (bs, 6H), 1.50-2.63 (m, 2H), 4.03 (q, 2H, J=7.1 Hz), 7.05-7.08 (m, 2H), 7.43 (d, 2H, J=7.3 Hz), 8.47 (bs, 2H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([C:19]3([CH2:31][CH2:32][CH3:33])[CH2:23][CH2:22][CH2:21][N:20]3C(OC(C)(C)C)=O)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([C:19]3([CH2:31][CH2:32][CH3:33])[CH2:23][CH2:22][CH2:21][NH:20]3)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CCCC1(C(=O)c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC1(C(=O)c2ccc3[nH]ccc3c2)CCCN1
Yield: 71.6 %

Procedure:
To a stirred solution of 5-(1-tert-butoxycarbonyl-2-propyl-pyrrolidine-2-carbonyl)-indole-1-carboxylic acid tert-butyl ester (0.132 g, 0.289 mmol) in DCM (3 mL) at 20° C. under nitrogen was added TFA (1 mL). After 14 hours the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM. The combined organic phases were concentrated in vacuo then purified by chromatography (silica, 0 to 30% MeOH in DCM) to furnish (1H-indol-5-yl)-(2-propyl-pyrrolidin-2-yl)-methanone (0.053 g, 0.207 mmol, 72%) as a beige foam, MS=257 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH2:12])[CH3:11].Cl[C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[C:15]=1[C:21]1[NH:37][C:24]2=[CH:25][C:26]3[C:27](=[O:36])[N:28]([CH:33]([CH3:35])[CH3:34])[C:29](=[O:32])[C:30]=3[CH:31]=[C:23]2[N:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[C:15]=1[C:21]1[NH:22][C:23]2=[CH:31][C:30]3[C:29](=[O:32])[N:28]([CH:33]([CH3:35])[CH3:34])[C:27](=[O:36])[C:26]=3[CH:25]=[C:24]2[N:37]=1)[CH3:11]
Reactant: CC(N)Cc1cc(F)ccc1F
Reactant: CC(C)N1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C(C)C)C3=O
Yield: 98.8 %

Procedure:
Racemic 1-(2,5-difluorophenyl)propan-2-amine (0.051 g) and 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-isopropylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.2965 mmol) were submitted to general procedure A to give 0.144 g the title compound. 1H NMR (500 MHz, DMSO-d6) δ 13.04 (s, 1H), 11.20 (d, 1H), 11.10 (d, 1H), 8.13 (s, 1H), 7.82 (t, 2H), 7.36-7.31 (m, 2H), 7.22-7.14 (m, 1H), 7.09-7.03 (m, 1H), 6.17 (d, 1H), 4.51-4.42 (m, 3H), 4.18-4.10 (m, 1H), 3.09-2.93 (m, 2H), 1.32 (d, 3H), 1.25 (d, 6H). APCI MS: m/z 489.9 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[S:11][CH2:10][CH2:9][CH2:8][S:7]1)=[O:5])[CH3:2].C([Li])CCC.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:17]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][CH2:8][CH2:9][CH2:10][S:11]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)SCCCS1
Temperature: -25 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
A solution of 3.0 g (15.6 mmol) of 2-ethoxycarbonyl-1,3-dithiane in 40 ml of dry tetrahydrofuran was cooled under inert atmosphere to -78° C. and treated with 7.5 ml (15.6 mmol) of n-butyllithium. The resulting solution was warmed to -25° C., stirred for 20 min, recooled to -78° C., treated with 1.8 ml (15.6 mmol) of benzyl chloride, and stirred at ambient temperature for 16 h. After quenching with aqueous ammonium chloride, the mixture was extracted with ether, washed sequentially with water, aqueous sodium thiosulfate, and brine, dried over MgSO4, and concentrated in vacuo. Flash chromatography using 5% ethyl acetate in hexane gave 3.9 g (88%) of the desired compound. 1H NMR (CDCl3) δ 1.33 (t, J=7 Hz, 3H), 1.85 (qt, J=14, 3 Hz, 1H), 2.11 (dm, J=14 Hz, 1H), 2.69 (dt, J=14, 4 Hz, 2 H), 3.23 (ddd, J=14, 12, 3 Hz, 2H), 3.38 (s, 2H), 4.27 (q, J=7 Hz, 2H), 7.25-7.35 (m, 5H). Mass spectrum (M+NH4)+ =300.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([CH3:13])[CH:7]=1.CC(OC(C)=O)=O.C([O-])(=O)C.[K+].[N:29](OC(C)(C)C)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:9](=[CH:10][CH:11]=1)[NH:12][N:29]=[CH:13]2
Reactant: CC(C)(C)ON=O
Reactant: Cc1cc(Oc2cccc(Cl)c2)ccc1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Clc1cccc(Oc2ccc3[nH]ncc3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
4-(3-Chloro-phenoxy)-2-methyl-phenylamine (0.87 g, 3.74 mmol) was dissolved in chloroform. Ac2O (0.878 g, 8.61 mmol) was then added dropwise over 10 min at 0° C. and the mixture was stirred for 1 h at 25° C. Potassium acetate (110 mg, 1.12 mmol) and t-butyl nitrite (829 mg, 8.05 mmol) were added to the reaction mixture and the mixture was heated at 80° C. for 16 h. This mixture was then concentrated, conc. HBr was added and the mixture was stirred for 16 h at 25° C. The pH of the mixture was adjusted to pH 7 using KOH solution and the resulting mixture was extracted with EtOAc (3×50 mL). The organic phase was washed with brine (3×10 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (11% EtOAc in hexanes) to afford 5-(3-chloro-phenoxy)-1H-indazole (152 mg, 17%). MS (M+H)+=245; 1H NMR (CDCl3) δ: 8.03 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.37 (br.s., 1H), 7.21 (d, J=6.18 Hz, 1H), 7.16 (dd, J=6.5, 1.1 Hz, 1H); 7.08 (d, J=5.8 Hz, 1H), 6.93 (br.s., 1H), 6.86 (d, J=6.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]([CH3:21])[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C1COCC1>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:13]([CH3:21])[CH2:14][CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(N(C)CC2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(C)CC2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-methoxy-N7-methyl-N7-(tetrahydro-pyran-4-ylmethyl)-benzothiazole-2,7-diamine with 4-fluorobenzoic acid, HATU and N-ethyldiisopropylamine in THF. ES-MS m/e (%): 430 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[F:25][C:26]1[CH:59]=[CH:58][C:29]([C:30](/[N:32]=[C:33]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(S(C)(=O)=O)N=CC=3N/2)=[O:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:30](/[N:32]=[C:33]2\[NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=3[N:12]\2[C@H:13]2[CH2:14][CH2:15][C@@H:16]([C:19](=[O:20])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:18]2)=[O:31])=[CH:58][CH:59]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ccc2N)CC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(S(C)(=O)=O)cc32)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(S(C)(=O)=O)cc32)CC1

Procedure:
The title compound was prepared from cis-4-(2-amino-5-(methylsulfonyl) phenylamino)-N-isopropylcyclohexanecarboxamide using a method analogous to that used in the preparation of (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide, as an off-white solid (0.111 g, 75% yield). MS, m/z (C25H29FN4O4S): calcd, 500.59. found 501.2 [M+H]. 1H NMR (400 MHz, DMSO-d6) d ppm 1.09 (d, J=6.55 Hz, 6H) 1.62-1.81 (m, 4H) 2.14 (m, J=13.10 Hz, 2H) 2.51-2.57 (m, 2H) 2.75-2.91 (m, 2H) 3.28 (s, 3H) 3.99-4.10 (m, 1H) 4.72-4.88 (m, 1H) 7.22-7.29 (m, 2H) 7.64 (d, J=7.73 Hz, 1H) 7.68-7.79 (m, 2H) 8.23-8.27 (m, 1H) 8.32-8.40 (m, 2H) 13.04 (br. s, 1H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=6.55 Hz, 6H) 1.62-1.81 (m, 4H) 2.09-2.19 (m, 2H) 2.51-2.57 (m, 2H) 2.75-2.91 (m, 2H) 3.28 (s, 3H) 4.05 (sxt, J=6.94 Hz, 1H) 4.72-4.88 (m, 1H) 7.25 (s, 2H) 7.64 (d, J=7.73 Hz, 1H) 7.68-7.79 (m, 2H) 8.23-8.27 (m, 1H) 8.32-8.40 (m, 2H) 13.04 (br. s, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](I)=[N:7][C:8]([Br:11])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)#[CH:14].N#N>C(N(CC)CC)C.[Cu]I.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>[C:1]([O:4][C:5]1[C:6]([C:14]#[C:13][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:7][C:8]([Br:11])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: C#Cc1ccc(F)cc1
Reactant: CC(=O)Oc1ccc(Br)nc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(Br)nc1C#Cc1ccc(F)cc1
Temperature: 85 °C
Yield: 73.4 %

Procedure:
6-bromo-2-iodopyridin-3-yl acetate (3.50 g, 10.24 mmol), 1-ethynyl-4-fluorobenzene (1.11 g, 9.21 mmol), copper (I) iodide (117 mg, 0.614 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (359 mg, 0.512 mmol) were combined and evacuated/backfilled with N2 (3×) then diluted with triethylamine (100 ml) and heated to 85° C. for 2 hours. The solvent was evaporated and the reaction was dissolved in EtOAc. The organic phase was washed with water (50 mL) and brine, dried over Na2SO4, filtered, and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 6-bromo-2-((4-fluorophenyl)ethynyl)pyridin-3-yl acetate (2.26 g, 6.76 mmol, 66.1% yield) consistent by NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (2H, s), 7.70 (2H, dd, J=8.78, 5.52 Hz), 7.34 (2H, t, J=8.91 Hz), 2.41 (3H, s). LC-MS retention time: 2.18 min; m/z: parent ion not observed, -Ac: 292, 294. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:21]4[CH:29]=[CH:30][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:32][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:15]2[CH:14]=[CH:13][C:12]([O:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([OH:4])[CH:6]=3)=[CH:17][CH:16]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(OC(C)=O)c3)cc1)n2C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(O)c3)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
Ethyl 2-[4-(3-acetoxyphenyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate (87 g) obtained in Example 27 was dissolved in methyl alcohol (250 ml) and tetrahydrofuran (250 ml), and potassium carbonate (31 g) was added. The mixture was stirred for 30 min at room temperature. The insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was neutralized with 2N hydrochloric acid. The precipitated crystals were collected by filtration to give the title compound (78 g, yield 97%).