Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][CH:14]([N:21]=[C:22]=S)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:22]([NH:21][C@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:13])[NH:2][C:3]=2[CH:7]=1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CC(N=C=S)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](NC1=NS(=O)(=O)c2sc(Cl)cc2N1)c1ccccc1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and L-α-methylbenzyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 195°-204° C. (ethyl acetate), 1H-NMR (DMSO-d6): δ 1.46 (d, 3H), 4.95 (m, 1H), 7.1 (s, 1H), 7.2-7.45 (m, 5H), 7.78 (br. s, 1H), 10.85 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([O:53][CH3:54])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:19]([CH:21](/[CH:33]=[CH:34]/[C:35]1[C:40]([O:41][CH3:42])=[CH:39][C:38]([O:43][CH3:44])=[CH:37][C:36]=1[O:45][CH3:46])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([N+:30]([O-])=O)[CH:23]=1)=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CC(C)=O.O>[CH3:46][O:45][C:36]1[CH:37]=[C:38]([O:43][CH3:44])[CH:39]=[C:40]([O:41][CH3:42])[C:35]=1/[CH:34]=[CH:33]/[CH:21]([S:19]([CH:7](/[CH:6]=[CH:5]/[C:4]1[C:47]([O:53][CH3:54])=[CH:48][C:49]([O:51][CH3:52])=[CH:50][C:3]=1[O:2][CH3:1])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH2:16])[CH:9]=1)=[O:20])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c([N+](=O)[O-])c2)S(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Temperature: 50 °C

Procedure:
(E)-2,4,6-Trimethoxystyryl-4-methoxy-3-nitrobenzylsulfoxide (1.3 mmol) was dissolved in a 2 to 1mixture of acetone and water (50 mL). The resulting mixture was heated to 50° C. After heating at 50° C. for 30 min, sodium dithionite (26.3 mmol) was added to the heated reaction mixture (portionwise over 20 minutes). The resulting mixture was maintained at 50° C. for 1hour, then cooled to room temperature (25° C.). Water (50 mL) was added to the cooled mixture. The resulting mixture was extracted with ethyl acetate (3×50 mL). The ethyl acetate extracts were combined and washed with saturated aqueous NaHCO3. The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield the crude product. The crude product was recrystallized from 2-propanol to afford the desired (E)-2,4,6-trimethoxy styryl-3-amino-4-methoxybenzylsulfoxide, as listed in Table 6.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:22]#[N:23])[CH:3]=1.[C:24]([CH2:27][C:28](=O)[CH3:29])(=O)[CH3:25].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[F:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:6]2[C:2]3=[N:1][C:24]([CH3:25])=[CH:27][C:28]([CH3:29])=[C:3]3[C:4]([C:22]#[N:23])=[CH:5]2)=[CH:13][CH:12]=1
Reactant: CC(=O)CC(C)=O
Reactant: N#Cc1cc(N)n(C(c2ccc(F)cc2)c2ccc(F)cc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c2c(C#N)cn(C(c3ccc(F)cc3)c3ccc(F)cc3)c2n1

Procedure:
To a solution of 5-amino-1-[bis(4-fluorophenyl)methyl]-1H-pyrrole-3-carbonitrile (13.9 g, 45.1 mmol) in ethanol (200 ml) was sequentially added acetylacetone (5.02 g, 50.2 mmol) and concentrated hydrochloric acid (2.0 ml). The mixture was heated under reflux for 3 hours, poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the objective product as a solid material.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(O[C:27]([N:29](C)[NH:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH3:41])=[CH:33][CH:32]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[CH3:27][N:29]1[C:10]2[C@@:9]3([CH3:8])[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:18](=[O:19])[N:30]1[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH3:41])=[CH:33][CH:32]=1
Reactant: Cc1ccc(NN(C)C(=O)OC(C)(C)C)c2ccccc12
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.6 %

Procedure:
Triethylamine (0.18 mL, 1.29 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 160 mg, 0.75 mmol) in 1,2-dichloroethane (2 mL) over 1 min. A solution of N-methyl-N′-(4-methyl-naphthalen-1-yl)-hydrazinecarboxylic acid tert-butyl ester (74 mg, 0.26 mmol) in 1,2-dichloroethane (4 mL) was added. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 15 min, and then in an oil bath at 50° C. for 30 min. The reaction mixture was cooled. A solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the mixture was heated in an oil bath at 100° C. for 1 h and allowed to cool. Dichloromethane (100 mL) was added and the mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 40-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated with methanol and then diethyl ether. The residue was dried under high vacuum at 70° C. overnight to give (4S,7R)-1,7,8,8-tetramethyl-2-(4-methyl-naphthalen-1-yl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (33 mg, 37%) as a light brown solid. ES(+)-MS (M+H) 347.
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:6])[CH:4]=[CH2:5].C(O[CH:11]1[NH:14][C:13](=[O:15])[CH:12]1[CH2:16][CH3:17])(=O)C>O>[CH2:3]([S:6][CH:11]1[NH:14][C:13](=[O:15])[CH:12]1[CH2:16][CH3:17])[CH:4]=[CH2:5]
Reactant: CCC1C(=O)NC1OC(C)=O
Reactant: C=CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCSC1NC(=O)C1CC
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3.2 g of sodium hydroxide in 40 ml of water under an argon atmosphere were added 8 ml of allyl thiol (about 85% pure). After 20 minutes of further stirring, a solution of 12.5 g of 4-acetoxy-3-ethylazetidin-2-one in 20 ml of water was added and the mixture was stirred for a further 15 minutes, and then extracted into dichloromethane. The organic extracts were washed with water, were dried over MgSO4, and evaporated in vacuo to dryness. Chromatography over silica gel, eluting with hexane-ethyl acetate mixtures, afforded the title compounds as a yellow oil (3.2 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=1[CH3:39])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.C([O-])(O)=O.[Na+].CN(C=O)C>[CH2:1]([N:8]1[CH2:18][CH:17]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[O:16][C:10]2([CH2:11][CH2:12][N:13]([C:34]([C:33]3[CH:37]=[CH:38][C:30]([O:29][CH:26]([CH3:27])[CH3:28])=[C:31]([CH3:39])[CH:32]=3)=[O:35])[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Reactant: Cc1ccc(C2CN(Cc3ccccc3)CC3(CCNCC3)O2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C2CN(Cc3ccccc3)CC3(CCN(C(=O)c4ccc(OC(C)C)c(C)c4)CC3)O2)cc1
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 8-benzyl-10-(p-tolyl)-11-oxa-3,8-diazaspiro[5.5]undecane (100 mg, 0.30 mmol), 4-isopropoxy-3-methyl-benzoic acid (61 mg, 0.31 mmol) and HATU (119 mg, 0.31 mmol) was stirred in DCM (450 μL) and DMF (450 μL) for 5 minutes. Triethylamine (83 μL, 0.59 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with sat. aq. NaHCO3 (5 mL) and extracted with DCM (3×5 mL), dried over MgSO4, filtered, concentrated in vacuo and purified by silica gel column chromatography (0-100% EtOAc/hexane) to give [8-benzyl-10-(p-tolyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone as a colorless oil (120 mg, 79%). ESI-MS m/z calc. 512.3. found 513.3 (M+1)+; Retention time: 1.86 minutes (3 min run).
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][O:10][C:11](=[O:51])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]2[C@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[F:33])[C@:24]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=3[F:43])([C:34]#[N:35])[C@H:23]([CH2:44][C:45]([CH3:48])([CH3:47])[CH3:46])[NH:22]2)=[O:20])=[C:14]([O:49][CH3:50])[CH:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[C:6]([CH2:8][CH2:9][O:10][C:11](=[O:51])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]2[C@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=3[F:33])[C@:24]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=3[F:43])([C:34]#[N:35])[C@H:23]([CH2:44][C:45]([CH3:46])([CH3:47])[CH3:48])[NH:22]2)=[O:20])=[C:14]([O:49][CH3:50])[CH:13]=1)([OH:7])=[O:5]
Reactant: COc1cc(C(=O)OCCC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)OCCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-tert-butoxycarbonyl-ethyl ester was treated with trifluoroacetic acid to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-carboxy-ethyl ester. MS (ES+) m/z calcd. for C34H34Cl2F2N3O6: [(M+H)+]: 688. found: 688.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([OH:17])=O)[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:14][C:15]([Cl:21])=[O:17])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(CC(=O)Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (3-acetoxy-4-nitro-phenyl)acetic acid (2.0 g, Reference Example 18) in dichloromethane (20 mL) was treated with a solution of oxalyl chloride in dichloromethane (4.4 mL, 2M) and then with dry dimethylformamide (1 drop). After a vigorous effervescence the mixture was stirred at room temperature for 4 hours, then evaporated to give the title compound as a viscous oil which was used immediately without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][N:11]=[C:10]([C:19]([OH:21])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][C:23]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH2:32])[N:30]=1)([CH3:25])[CH3:24]>>[C:23]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH:32][C:19](=[O:21])[C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[CH:12][N:11]=2)[N:30]=1)([CH3:25])([CH3:22])[CH3:24]
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC2CC2)cn1
Reactant: CC(C)(C)c1nc(CN)cs1
Product: CC(C)(C)c1nc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC3CC3)cn2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(cyclopropylmethyloxy)-pyridine-2-carboxylic acid (example H) and 2-(1,1-dimethylethyl)-4-thiazolemethanamine (CAN 937656-81-0) as starting materials; LC-MS (UV peak area/ESI) 100%, 456.1491 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:15]([C:12]2[S:11][C:10]([NH:9][C:8]([N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[N:14][CH:13]=2)=[O:17])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carboxylic acid (176 mg, 0.50 mmol), piperazine carboxylic acid tert-butyl ester (140 mg, 0.75 mmol), and HBTU (285 mg, 0.75 mmol) were weighed out and added to a 25 mL reaction flask. DMF (5 mL) and DIEA (175 μL, 1.0 mmol) were added. The reaction was stirred under nitrogen at ambient temperature overnight. The reaction was diluted with EtOAc (10 mL) and quenched with saturated aqueous NH4Cl (10 mL). After separation and extraction with EtOAc (2×5 mL) the combined organic portions were dried over MgSO4. Purification with silica gel and 10% EtOAc in CH2Cl2 afforded 187 mg (72%) of the desired compound.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:8]=[C:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:6]([CH3:21])[N:5]=1>C(Cl)(Cl)(Cl)Cl>[NH2:3][C:4]1[C:8]([Br:1])=[C:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][C:10]=2[Cl:20])[N:6]([CH3:21])[N:5]=1
Reactant: BrBr
Reactant: Cn1nc(N)cc1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(N)c(Br)c1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 136.9 %

Procedure:
Bromine (0.12 g) was added to a solution of 0.3 g of 3-amino-5-(2,6-dichloro-4-trifluoromethylphenyl)-1-methylpyrazole in 5 ml of anhydrous carbon tetrachloride at room temperature, and the mixture was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure to obtain a residue, which was then purified by column chromatography on silica gel (eluent: ether/hexane=1/5), affording 0.4 g of the desired compound in the form of white crystals (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:36][N:37]([CH3:61])[C:38]([CH:40]1[O:45][CH2:44][CH2:43][N:42]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48](B3OC(C)(C)C(C)(C)O3)[CH:47]=2)[CH2:41]1)=[O:39].[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.CCOCC.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:48]4[CH:49]=[CH:50][CH:51]=[C:46]([N:42]5[CH2:43][CH2:44][O:45][CH:40]([C:38](=[O:39])[N:37]([CH3:36])[CH3:61])[CH2:41]5)[CH:47]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(=O)C1CN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CCO1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1CN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)c4n3)c2)CCO1
Temperature: 160 °C
Yield: 36.8 %

Procedure:
A mixture of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50.0 mg, 0.101 mmol), N,N-dimethyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine-2-carboxamide (73.4 mg, 0.204 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.21 mg, 0.0102 mmol), and 2M NaOH aq. (0.150 mL, 0.310) in DMF (2 mL) was heated at 160° C. for 2 hours under microwave irradiation. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (5×). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (CHCl3/EtOAc=1:1→1:2→EtOAc) to afford crude product. The crude product was slurried in ether and collected by filtration. After the solid was washed with ether to afford desired product (25.6 mg, 36.5%) as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][N:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(N)ncc1Br
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCOC(=O)/C=C/c1cnc(N)cc1C
Temperature: 25 °C
Yield: 58.4 %

Procedure:
To a stirred solution of 2-amino-5-bromo-4-methylpyridine (10 g, 54 mmole) in propionitrile (50 mL) was added ethyl acrylate (17 mL, 157 mmole), DIEA (19 mL, 106 mmole), palladium(II) acetate (0.61 g, 2.7 mmole) and tri-o-tolylphosphine (1.64 g, 5.4 mmole). The reaction was purged with argon and heated at reflux for 6 hr, then was cooled to RT and concentrated to dryness under vacuum. The resulting residue was taken up in ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated and the remaining residue was triturated with 1:1 Et2O/petroleum ether (50 mL), filtered, and dried under vacuum to give the title compound (6.50 g, 59%) as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.66 (d, J=16.0 Hz, 1H), 6.40 (br s, 2H), 6.32 (d, J=16.0 Hz, 1H), 6.28 (s, 1H), 4.15 (q, 2H), 2.24 (s, 3H), 1.24 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][NH:10][C@@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.Br[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[C:18]([C:33]#[N:34])=[CH:17]2.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F.C(O[Na])(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[C:33]([C:18]1[N:19]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:25])[CH3:26])[C:20]2[C:16]([CH:17]=1)=[CH:15][C:14]([N:10]1[C@@H:9]3[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]3)[NH:3][C:2]([CH3:12])([CH3:1])[CH2:11]1)=[CH:22][CH:21]=2)#[N:34]
Reactant: CC1(C)CN[C@H]2CCCC[C@@H]2N1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1c(C#N)cc2cc(Br)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1c(C#N)cc2cc(N3CC(C)(C)N[C@H]4CCCC[C@@H]43)ccc21
Yield: 77.7 %

Procedure:
A toluene (5 ml) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 5-bromo-1-(triisopropylsilyl)-1H-indole-2-carbonitrile (493 mg, 1.31 mmol), Pd(OAc)2 (13.3 mg, 0.0594 mmol), tBu3P.HBF4 (17.2 mg, 0.0594 mmol), and t-BuONa (137 mg, 1.43 mmol) was stirred at 100° C. for 4 hours in a nitrogen atmosphere. Insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane) to obtain (4aS,8aS)-1-(2-cyano-1-(triisopropylsilyl)-1H-indol-5-yl) 3,3-dimethyldecahydroquinoxaline (430 mg, 78%) in a white amorphous solid form.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[OH:33])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[CH:37][C:38]2[O:42][C:41]([C:43]3[CH:48]=[CH:47][C:46]([CH2:49]Cl)=[CH:45][CH:44]=3)=[N:40][C:39]=2[CH:51]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][CH2:49][C:46]1[CH:45]=[CH:44][C:43]([C:41]2[O:42][C:38]3[CH:37]=[CH:36][C:35]([Cl:34])=[CH:51][C:39]=3[N:40]=2)=[CH:48][CH:47]=1)[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1cc(F)ccc1O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1cc(F)ccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
4.17 g (9.09 mmol) of rac-ethyl 5-{(tert-butoxycarbonyl)[2-(5-fluoro-2-hydroxyphenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate, 3.04 g (10.91 mmol) of 5-chloro-2-[4-(chloromethyl)phenyl]-1,3-benzoxazole and 3.14 g (22.74 mmol) of potassium carbonate in 120 ml of acetonitrile were heated to 110° C. and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed repeatedly with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). This gave 5.43 g (7.75 mmol, 85% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:18])[CH2:17][CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.C(Cl)(Cl)Cl.[CH2:30]([O:32][CH2:33][C:34](Cl)=O)[CH3:31]>ClCCl>[CH2:30]([O:32][CH2:33][C:34]1[N:12]([CH2:13][C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:31]
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a mixture of 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclobutanol (23.1 mmol, prepared as described in Part D) in dichloromethane (154 mL) and triethylamine (3.54 mL, 25.4 mmol) at 0° C. was added chloroform (100 mL). The mixture was allowed to warm to rt and approximately two thirds of the starting material dissolved. To the mixture was slowly added ethoxyacetyl chloride (88%, 3.1 g, 24.3 mmol). The solution was stirred at rt for 2 h. More triethylamine (2 mL) and ethoxyacetyl chloride (88%, 1.0 g) were added. After an additional 16 h, the reaction solution was concentrated in vacuo. To the residue was added ethanol (190 mL) and triethylamine (13 mL). The resulting solution was heated at reflux for 20 h and then concentrated in vacuo to a yellow solid. The solid was partitioned between dichloromethane (400 mL) and water (100 mL). The organic layer was washed with water (100 mL) and brine (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was crystallized from acetonitrile and the crystals were isolated by filtration to provide 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol (4.52 g, 63%).