Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@H:13]([CH2:15][CH2:16]O)[CH3:14])=[CH:10][CH:11]=2)[N:6]([CH3:18])[C:5]1=[O:19].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>ClCCl>[N:34]([CH2:16][CH2:15][C@@H:13]([C:9]1[N:8]=[C:7]2[N:6]([CH3:18])[C:5](=[O:19])[N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[C:12]2=[CH:11][CH:10]=1)[CH3:14])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](CCO)c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](CCN=[N+]=[N-])c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 36-2 (0.15 g, 0.52 mmol) in dichloromethane (2 mL) was added triethylamine (0.15 mL, 1.08 mmol) and methanesulfonyl chloride (0.05 mL, 0.62 mmol). The resulting mixture was stirred at room temperature for 10 minutes and concentrated. The residue was dissolved in DMF (2 mL). To this solution was added sodium azide (0.20 g, 3.08 mmol) and the mixture was heated to 90° C. for 3 days. The reaction was allowed to cool and partitioned between ethyl acetate and water. The organic phase was concentrated to give 36-3. (0.13 g, 83%). LRMS (ES) (M+H)+: observed=317.1, calculated=317.4.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[C@@H:15]([O:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[C@@H:15]([O:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C@H:16]([OH:17])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](Oc1ccc(F)cc1)[C@H](O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](Oc1ccc(F)cc1)[C@H](O)c1ccc(O)cc1

Procedure:
The target compound (1.94 g) was obtained as a foam by carrying out the reaction and the post-treatment according to Reference example 20(c) using (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxyphenyl)-2-(4-fluorophenoxy)-3-hydroxypropionyl]oxazolidin-2-one (2.33 g) obtained from Reference example 22(b) and palladium-charcoal (5%, 490 mg).
Reaction SMILES: Cl.O[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14].[OH-].[Na+]>C(O)(=O)C.Cl>[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22][CH2:3][C:4]2[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6][CH:5]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: OCc1cnc2ccccn12
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(SCc2cnc3ccccn23)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 69.9 %

Procedure:
A mixture of 3-hydroxymethylimidazo[1,2-a]pyridine hydrochloride (0.50 g) and 4-nitrothiophenol (0.42 g) in acetic acid (10 ml) and concentrated hydrochloric acid (10 ml) was stirred for 5 hours at 100° C. The reaction solution was cooled to 0° C., 8N aqueous solution of sodium hydroxide was added dropwise to adjust pH to 8. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether, to give 3-(4-nitrophenylthiomethyl) imidazo[1,2-a]pyridine (0.54 g) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[S:5][C:6]=1[CH2:7][S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH:14](O)[CH2:13][CH2:12]2.[CH3:30][O:31][C:32]([CH:34]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:33]>CCOCC>[CH3:30][O:31][C:32](=[O:33])[CH2:34][CH:14]1[CH:13]=[CH:12][C:11]2[CH:10]=[C:9]([S:8][CH2:7][C:6]3[S:5][C:4]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=4)=[N:3][C:2]=3[CH3:1])[CH:18]=[CH:17][C:16]=2[O:15]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc2c(c1)CCC(O)O2
Solvent: CCOCC
Product: COC(=O)CC1C=Cc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc2O1
Temperature: 60 °C
Yield: 64.4 %

Procedure:
Mixture of compound 5F (130 mg, 0.3 mmol) and methyl (triphenylphosphoranylidene) acetate (110 mg, 0.33 mmol) in CDCl3 (15 mL) was heated to 60° C. for 2 h. After the reaction mixture was cooled to RT, ether (100 mL) was added and the mixture was passed through a short silica gel column eluted with ether. Solvent was removed to afford compound 5G as an off-white solid (95 mg, 65%). MS: 494 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:4](=[O:14])[C:5]2[C:6]([N:13]=1)=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2.[CH:22]([NH:24][NH2:25])=O>C(#N)C>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:3]1[C:4](=[O:14])[C:5]2[C:6](=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[N:13]2[CH:22]=[N:24][N:25]=[C:2]12
Reactant: NNC=O
Reactant: CSc1ncc2c(=O)n(-c3ccccc3Cl)c(Cl)nc2n1
Solvent: CC#N
Product: CSc1ncc2c(=O)n(-c3ccccc3Cl)c3nncn3c2n1

Procedure:
A mixture of Example 1B (0.150 g, 0.442 mmol) and formohydrazide (0.066 g, 1.11 mmol) in acetonitrile (7 mL) was heated at 150° C. for 15 minutes in a Biotage microwave reactor. The solid was filtered. The filtrate was concentrated, treated with saturated aqueous NaHCO3 and extracted with ethyl acetate (2×). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/ethyl acetate (3:7 to 2:8) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]12[CH:14]([CH2:15][CH3:16])[N:6]([CH:7]([CH2:12][CH3:13])[NH:8][CH:9]1[CH2:10][CH3:11])[CH:5]([CH2:17][CH3:18])[N:4]=[CH:3]2.[BH4-].[Na+]>[OH-].[Na+].C(O)C>[CH2:3]([C:2]1([CH3:1])[CH:9]([CH2:10][CH3:11])[NH:8][CH:7]([CH2:12][CH3:13])[NH:6][CH:14]1[CH2:15][CH3:16])[NH:4][CH2:5][CH2:17][CH3:18]
Reactant: CCC1N=CC2(C)C(CC)NC(CC)N1C2CC
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCNCC1(C)C(CC)NC(CC)NC1CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.3 %

Procedure:
To a mixture of 70 grams of 5-methyl-2,6,8,9-tetraethyl-1,3,7-triazabicyclo (3,3,1) non-3-ene, 0.5 grams of sodium hydroxide, and 190 grams of ethanol was added, with stirring, over a 1/2 hour period 9 grams of sodium borohydride. The mixture was stirred for 20 hours at ambient temperature. The ethanol was removed under diminished pressure and the resulting product was added to water and extracted with ether. The ethereal solution, after drying over anh. MgSO4, was evaporated under diminished pressure to yield 64.2 grams of 5-(2-azapentyl)-5-methyl-2,4,6-triethylhexahydropyrimidine, b.p. 138°-150° C./20 torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21]([OH:23])=O)=[N:6][CH:7]=1.[CH3:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[N:11][C:10]=2[C:21]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:34][CH:33]=2)=[O:23])=[N:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(NC(=O)c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazole-4-carboxylic acid (intermediate A 4.1, 15 mg, 0.043 mmol), 4-(methylsulfonyl)aniline (7.32 mg, 0.043 mmol) and DIPEA (0.015 ml, 0.086 mmol) in 0.6 mL of DMF was added BOP (22.7 mg, 0.051 mmol). The reaction was stirred at room temperature for 1 h and purified by reverse phase HPLC to give 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-N-[4-(methylsulfonyl)phenyl]-1,3-oxazole-4-carboxamide: 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.38 (d, J=2.5 Hz, 1H), 8.08 (m, 2H), 7.94 (s, 4H), 7.61 (dd, J=8.4, 2.5 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.19 (m, 2H), 3.06 (s, 3H); HRMS exact mass calc for C22H15ClFN3O4S2 [M+H]+: 504.0245; observed: 504.0249.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH:24]([CH3:26])[CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH:24]([CH3:26])[CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: CC(C)c1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Product: CC(C)c1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 20.6 %

Procedure:
Using cyclohexyl{3-(1-methylethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.65 g) synthesized in Example 7(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.34 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.16 g, 21%) was obtained as a white solid.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28]([C:30]1[CH:34]=[CH:33][S:32][CH:31]=1)=N>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([C:30]4[CH:34]=[CH:33][S:32][CH:31]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: N=C(NO)c1ccsc1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccsc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-thiophene-3-carboxamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.78 min; Mass spectrum (ESI+): m/z=462 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([C:17](=[O:27])[CH:18]=[C:19]2[C:23](=O)[O:22]C(C)(C)[O:20]2)[O:15][CH3:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>>[C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([C:17](=[O:27])[CH:18]=[C:19]([OH:20])[C:23]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:22])[O:15][CH3:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(N)(=O)=O
Reactant: CON(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)C=C(O)C(=O)NS(C)(=O)=O
Yield: 66.9 %

Procedure:
Reaction of 4-({[2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)-benzoic acid tert-butyl ester (0.060 g, 0.15 mmol) with methanesulfonamide (0.014 g, 0.15 mmol) as described in the prepartion of compound 22 gave 0.043 g (67% yield) of the title amide as a white solid. 1H NMR (400 MHz, CDCl3) δ: mixture of rotamers: 1.58 (9H, s t-Bu), 3.31, 3.33 and 3.36 (3H, 3 S, SO2CH3), 3.61, 3.66 and 3.70 (3H, 3 s, OCH3), 4.8 and 4.88 (2H, 2 s, NCH2), 6.6 (1H, s, CH), 7.28 (2H, m, aromatics), 7.98 (2H, m, aromatics), 8.98 (1H, broad s, NH). HRMS (ESI/neg) calculated for C18H23N2O8S: [M−H]−: 427.117513; found: 427.117342.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]([CH2:20][C:21]1([CH3:32])[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH:23]([N:29]=[C:30]=[O:31])[CH2:22]1)=[C:18]=[O:19]>>[CH2:10]([N:8]([O:9][C:30]([NH:29][CH:23]1[CH2:24][C:25]([CH3:27])([CH3:28])[CH2:26][C:21]([CH2:20][NH:17][C:18]([O:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])([CH3:32])[CH2:22]1)=[O:31])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Product: CC1(C)CC(NC(=O)ON(Cc2ccccc2)Cc2ccccc2)CC(C)(CNC(=O)ON(Cc2ccccc2)Cc2ccccc2)C1

Procedure:
The procedure of Example 1 is repeated using 10.66 g (50 mmol) of N,N-dibenzylhydroxylamine and 5.56 g (25 mmole) of 3-isocyanatomethyl-3,5,5-trimethylcyclohexylisocyanate. The residue is recrystallized from a 1:1 heptane:toluene solvent mixture to give 11.0 g (68%) of a white soldi, m.p. 139°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[C:7]=2[NH:6][CH:5]=[CH:4]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1ccc(Cl)c2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2ccc(Cl)c3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
To a solution of 64 mg (0.33 mmol) of 4-chloro-1H-indole-7-carboxylic acid and 91 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine in 3 ml DCM 63 mg (0.33 mmol) of EDC.HCl were added and the reaction mixture was stirred over night at rt. The product was purified by column chromatography (25 g silica gel; heptane/EtOAc 7:3) to yield 104 mg (72%) product as a light yellow foam. MS (ISP) 479.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].CCN(C(C)C)C(C)C.C(Cl)(=O)C(C)(C)C.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([CH3:44])([CH3:43])[C:41]#[N:42])=[CH:36][C:35]=1[CH3:45]>C(Cl)Cl>[C:41]([C:40]([C:37]1[CH:38]=[CH:39][C:34]([CH2:33][NH:32][C:11](=[O:13])[CH2:10][N:7]2[C:6]3[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[C:35]([CH3:45])[CH:36]=1)([CH3:44])[CH3:43])#[N:42]
Reactant: Cc1cc(C(C)(C)C#N)ccc1CN
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(C)(C)C#N)ccc1CNC(=O)Cn1cnc2ccc(F)c(F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
(6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (91 mg, 0.43 mmol) prepared according to scheme 2 is dissolved in DCM (3 mL). DIPEA (0.1 mL) is added, followed by pivaloyl chloride (53 μL, 0.43 mmol). After 1 hour, 2-[4-(aminomethyl)-3-methylphenyl]-2-methylpropanenitrile (80 mg, 0.43 mmol) prepared according to scheme 19 is added. The mixture is stirred overnight at room temperature, concentrated under vacuo and purified on HPLCMS: Waters prep LCMS, 27 ml/min, Column: X-Bridge Prep C18 OBD, 30×50 mm, 5 μm particle size, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, Gradient used 30% to 50% B in A, in 10 min. The fractions are combined and freeze dried to give the desired product (59 mg, 0.15 mmol, 35%). MS (ESI) (M+1) 369.2. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.67 (s, 6H) 4.33 (d, J=5.86 Hz, 2H) 5.10 (s, 2H) 7.23 (ddd, J=11.62, 8.89, 7.62 Hz, 1H) 7.32 (d, J=8.59 Hz, 2H) 7.44-7.51 (m, 3H) 8.21 (s, 1H) 8.80 (t, J=5.86 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: COCC1COc2cc3ncnc(Nc4cc(Cl)cc(Cl)c4)c3cc2O1
Yield: 85 %

Procedure:
The titled compound (20 mg, 80%, m.p. 269-274° C.) was prepared in a similar manner as in Example 8, except for employing 4-chloro-7-methoxymethyl-[1,4]dioxano[2,3-g]quinazoline (17 mg, 0.06 mmol) and 3,5-dichloroaniline (21 mg, 0.12 mmol).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Br:15])=[C:11](Br)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:17].[K+]>CN(P(N(C)C)(N(C)C)=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([Br:15])=[C:11]([OH:17])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=c1c(Br)c(Br)cnn1Cc1ccccc1
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=c1c(Br)c(O)cnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
The residue from step 1 was dissolved in HMPA (50 mL) and 8N KOH (65 mL) was added. The mixture was warmed to 120°-125° C. and stirred vigourously for 16 h. The mixture was cooled to r.t., the aqueous layer was separated, diluted with H2O (500 mL) and acidified to pH 6 with 6N HCl under vigourous stirring. After cooling in an ice bath, the solid was collected and air dried. It was dissolved in warm IN NaOH and washed once with ETOAc. The aqueous layer was acidified to pH 6 with 6N HCl and cooled again in an ice bath. The solid was filtered and air dried to yield the title compound (4.4 g, 40 %).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=C(C#N)[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([OH:22])(=[O:21])[CH3:20].S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:20]([C:19]([OH:22])=[O:21])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 110 °C
Reaction time: 6.5 h

Procedure:
To 10.0 g of 3-(3-fluorophenyl)-1H-5-indazolecarbonitrile were sequentially added 50 ml of glacial acetic acid, 15 ml of water and 12 ml of concentrated sulfuric acid, and the mixture was stirred at 110° C. for 6.5 hours. After standing to cool, the reaction mixture was added with 150 ml of ice-water, and the resulting crystals were collected by filtration. The resulting crystals were dried in vacuo, to give 10.7 g of the title compound as beige orange-pink crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C@@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:20][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Br)c1
Product: Brc1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3-Bromobenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:39][O:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c(OC)c1
Yield: 85.7 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with (2,4-dimethoxyphenyl)boronic acid (147 mg, 0.81 mmol), sodium carbonate (86 mg, 0.81 mmol) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 20%, dichloromethane-ethyl acetate) to give 95 mg (87% yield) of the title compound. Purity 87%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][C:32](O)=[O:33])=[CH:25][CH:24]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@@H:30]([NH:35][C:36](=[O:37])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:31][C:32]([N:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([C:8]3[N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=4[N:9]=3)[CH2:12]2)=[O:33])=[CH:25][CH:24]=1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2c(Cl)cccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2c(Cl)cccc21

Procedure:
(R)-4-chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (0.245 mmol, crude oil) (48A) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (0.319 mmol, 0.082 g) and N-methylmorpholine (1.47 mmol, 0.162 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.319 mmol, 0.121 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-Butyl (R)-1-(4-bromophenyl)-4-((R)-3-(4-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (48B) as a clear oil which was used without further quantification. ESI-ESI-MS: m/z 647.3 (M+H)+.