Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@H:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:36][OH:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@H:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:36][OH:37])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(N[C@@H](CO)c1ccccc1)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N[C@@H](CO)c3ccccc3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and (R)-2-bromo-N-(2-hydroxy-1-phenylethyl)benzenesulfonamide. MS (ESI): mass calcd. for C24H21FN4O3S, 464.13; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.36-8.32 (m, 1H), 8.07-8.01 (m, 2H), 7.75 (t, J=8.2, 1H), 7.60-7.54 (m, 1H), 7.49-7.44 (m, 1H), 7.25-7.18 (m, 4H), 7.07-7.00 (m, 3H), 6.98-6.92 (m, 1H), 4.19 (t, J=6.6, 1H), 3.69-3.58 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:14]3[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]4[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]4)[C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:14]3[N:15]=[C:16]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:17]=[C:18]([N:19]4[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]4)[C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(Sc4ccc(Br)cc4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(Sc4ccc(Br)cc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-(4-bromophenyl-thio)-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 272°-275° C.) and piperazine.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH3:36]N>O>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][N:22]([CH3:36])[C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CN
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN(C)C(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 130 °C
Yield: 85 %

Procedure:
A mixture of 3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 7 of Example 1, 627 mg, 9.0 mmol), a solution of methylamine (40% in methanol, 6 mL) and water (6 mL) was placed in a sealed tube and heated overnight at 130° C. The reaction mixture was partitioned between dichloromethane (50 mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic extracts were washed with brine (50 mL) and dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (5:1) to afford 523 mg (85%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.41 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 6.90 (1H, s), 4.73 (1H, br.s), 2.93 (4H, s), 2.82 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.51 (3H, s), 2.49 (3H, s), 1.28 (3H, t, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:36]([NH2:38])=[O:37])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[C:31]([CH2:33][NH:34][CH3:35])[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:39]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:36]([NH2:38])=[O:37])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[C:31]([CH2:33][N:34]5[CH2:3][CH2:2][CH2:39][CH2:35]5)[CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNC)cs4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CN5CCCC5)cs4)cc23)CC1
Yield: 24.1 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (0.083 mL) for 2 M methylamine to afford 14.8 mg of the title compound (24.1%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[NH2:16].CO[C:19](OC)(OC)[CH3:20].Cl.N1C=CC=CC=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:19]1[CH3:20]
Reactant: Nc1cnc2ccccc2c1NCCCCl
Reactant: COC(C)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nc2cnc3ccccc3c2n1CCCCl
Yield: 77.8 %

Procedure:
Using the general method of Example 1 Part D, N4-(3-chloropropyl)quinoline-3,4-diamine (˜37.6 mmol) was cyclized using 1,1,1-trimethoxyethane (5.43 g, 45.2 mmol) in the presence of pyridine hydrochloride (0.43 g) to provide 7.6 g of 1-(3-chloropropyl)-2-methyl-1H-imidazo[4,5-c]quinoline as a light yellow solid.
Reaction SMILES: I.C(OC(=O)C)(=O)C.[O:9]=[C:10]1[N:14]([CH2:15][C:16]([O:18]CC)=[O:17])[C:13]2[CH:21]=[C:22]([O:25]C)[CH:23]=[CH:24][C:12]=2[S:11]1.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[O:9]=[C:10]1[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13]2[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:12]=2[S:11]1
Reactant: CCOC(=O)Cn1c(=O)sc2ccc(OC)cc21
Agent: I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)Cn1c(=O)sc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
To a mixture of 57% hydriodic acid (50 ml) and acetic anhydride (15 ml) was added a solution of ethyl 2-oxo-5-methoxy-3-benzothiazolineacetate (2.67 g) in acetic acid (15 ml). The reaction mixture was refluxed with stirring for 1.5 hours and then cooled to ambient temperature. To the resultant mixture were added ice-water and a small volume of sodium bisulfite. The mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give crystalline 2-oxo-5-hydroxy-3-benzothiazolineacetic acid (1.7 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:17][O:18][C:19](=[O:51])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([S:39]([N:42]3[CH2:47][CH2:46][CH:45]([CH:48]=O)[CH2:44][CH2:43]3)(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[O:31])=[C:24]([F:50])[CH:23]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[F:50][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[CH2:28][NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]2[CH2:43][CH2:44][CH:45]([CH2:48][NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:46][CH2:47]2)(=[O:40])=[O:41])=[CH:35][CH:34]=1)=[O:31])[O:21][CH2:20][C:19]([O:18][CH3:17])=[O:51]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: COC(=O)COc1ccc(CNC(=O)Nc2ccc(S(=O)(=O)N3CCC(C=O)CC3)cc2)c(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)COc1ccc(CNC(=O)Nc2ccc(S(=O)(=O)N3CCC(CNC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)c(F)c1
Yield: 56.9 %

Procedure:
The title compound was prepared from N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide (0.128 g, 0.52 mmol), (4-{3-[4-(4-formyl-piperidine-1-sulfonyl)-phenyl]-ureidomethyl}-3-fluoro-phenoxy)-acetic acid methyl ester (0.5 mmol), glacial acetic acid (0.03 mL, 0.5 mmol) and sodium cyanoborohydride (0.031 g, 0.5 mmol) according to the general procedure used for example 84 (Step E) to give the final product (0.21 g).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].CN(P(N(C)C)(N(C)C)=O)C.[H-].[Na+].I[CH2:20][C@H:21]([NH:26][C:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[C:3]([CH:2]([C:1]#[N:5])[CH2:20][C@H:21]([NH:26][C:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]([O:24][CH3:25])=[O:23])#[N:4]
Reactant: N#CCC#N
Reactant: COC(=O)[C@H](CI)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C#N)C#N)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 60 %

Procedure:
To a solution of malononitrile (0.71 g; 10.6 mmol) in mixture of THF (30 mL) and HMPA (20 mL) was added sodium hydride 60% (0.43 g; 10.6 mmol) and stirred for min. To this mixture was added a solution of methyl (2R)-3-iodo-2-(tritylamino)propanoate CIII (5.0 g; 10.6 mmol) in THF (52 mL) and stirred overnight at r.t. The reaction was quenched with saturated aqueous ammonium chloride and extracted with diethyl ether (5×). The combined organic layers were washed with saturated aqueous ammonium chloride and dried over anhydrous MgSO4. The solvent was removed and the residue was purified on a silica gel column (3:1 hexane/EtOAc) and then crystallized from hexane/EtOAc to give the methyl (2S)-4,4-dicyano-2-(tritylamino)butanoate CIV (2.62 g; 6.4 mmol; 60% yield). 1H NMR (CDCl3) 3.02-3.06 (m, 1H), 2.70-2.75 (m, 1H), 2.81-2.86 (m, 1H), 2.95 (dd, J=12 Hz, J=6 Hz, 1H), 3.76 (s, 3H), 4.51 (d, J=6 Hz, 1H), 7.23 (t, J=8 Hz, 3H), 7.32 (dd, J=8 Hz, J=8 Hz, 6H), 7.43 (d, J=8 Hz, 6H); ESIMS found for C26H23N3O2 m/z 432.3 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[Br:13]N1C(=O)CCC1=O>CS(C)=O>[Br:13][C:8]1[C:7]([C:9]([F:10])([F:11])[F:12])=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1
Solvent: CS(C)=O
Product: Nc1cc(Cl)c(Br)c(C(F)(F)F)c1
Yield: 95.7 %

Procedure:
To a mixture of 3-chloro-5-(trifluoromethyl)aniline (3.25 g, 16.6 mmol, Eq: 1.00) in dimethylsulfoxide (43.4 ml) was added N-bromosuccinimide (3.11 g, 17.4 mmol, Eq: 1.05) in 5 portions over 2.5 hr (622 mg each 30 min). 2 h after the last addition, the reaction mixture was partitioned between 10% aqueous sodium sulfite and ethyl acetate. The organic layer was washed with aqueous sat. sodium carbonate, water (3 times) and brine then adsorbed unto silica (6 g) and purified on silica gel (column 120 g, Hexane/ethyl acetate 90:10 to 65:35) to give 4.36 g (96%) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](F)[N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Fc1cccc(F)n1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(F)n1

Procedure:
The title compound, off-white cristalline solid, MS: m/e=312.1, 314.1 (M+H+) was prepared in accordance with the general method of example 1b from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2,6-difluoropyridine.
Reaction SMILES: CN(C=O)C.[OH:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=1>O>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:18][CH:19]=1
Reactant: OCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(OCCN2CCCC2)nc1
Reaction time: 1 h

Procedure:
To a stirred DMF solution (25 mL) containing N-(2-hydroxyethyl)pyrrolidine (2.18 g, 18.9 mmol) under N2 was added 60% NaH in mineral oil (0.76 g, 18.9 mmol). The mixture was stirred for 1 hr while gas evolution ceased. Subsequently 2-chloro-5-nitropyridine (2.0 g, 12.6 mmol) was added. After stirring overnight, the dark solution was poured into H2O (100 mL) and extracted 3× with EtOAc. The combined organic layers were washed 2× with H2O prior to drying over Na2SO4. Concentration under vacuum yielded an orange oil which was chromatographed on silica gel employing ˜10% MeOH/CH2Cl2 to elute 1.62 g of 5-nitro-2-(pyrrolidin-1-yl)-ethoxy)pyridine (54%). The above product reduced to the corresponding substituted aminopyridine by hydrogenation in an EtOH solution (20 mL) containing 10% Pd/C (0.1 g) under 60 psi of H2 for 4 hr. Upon completion the reaction was filtered prior to concentration under vacuum. The resulting dark oil was chromatographed on silica. Gradient elution (CH2CL2 to 20% MeOH/CH2Cl2) eluted 1.03 g of the title compound as a broad peak.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[C:5](=[O:12])[NH:4][C:3]1=[O:13].Cl[CH2:15][CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[C:5](=[O:12])[N:4]([CH2:15][CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:3]1=[O:13]
Reactant: CC(C)=CCCCCl
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCCCn1c(=O)c2c(ncn2C)n(C)c1=O

Procedure:
9.0 g (0.05 mol) of 3,7-dimethylxanthine, 8.0 g (0.06 mol) of 1-chloro-5-methyl-4-hexene and 8.3 g (0.06 mol) of potassium carbonate are stirred in 200 ml of dimethylformamide at 110° C. for 22 hours. After the solvent has been removed in vacuo, 100 ml of 1N sodium hydroxide solution are added and the mixture is extracted thoroughly with methylene chloride. The extract is extracted again by shaking with dilute sodium hydroxide solution, washed with water until neutral, dried and evaporated under reduced pressure and the residue is recrystallized from diisopropyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10]OC)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl(O)(=O)(=O)=O.C(N(CC)CC)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC=C(c1ccccc1)c1cc(Br)cnc1N
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Brc1cnc2[nH]cc(-c3ccccc3)c2c1
Temperature: 100 °C
Yield: 77.9 %

Procedure:
1.093 g (3.582 mmol) of 5-bromo-3-(2-methoxy-1-phenylvinyl)-2-pyridylamine was dissolved in 60 ml of anhydrous 1,4-dioxane. 800 μl of 70% aqueous perchloric acid was added and the mixture heated to 100° C. for 13 hours. The mixture was then cooled to room temperature and 3 ml of triethylamine was added and the mixture evaporated to dryness. The resulting crude was crystallized from hot ethanol to afford 763 mg (2.79 mmol, 78% yield) of 5-bromo-3-phenylpyrrolo[2,3-b]pyridine as a beige-brown to brown crystalline solid. 1H-NMR (d6-DMSO) δ: 12.19 [1H] s, 8.44 [1H] d, 8.34 [1H] d, 7.97 [1H] d, 7.72 [2H] d(m), 7.45 [2H] t, 7.27 [1H] t(m). MS: m/z 273 [MH+].
Reaction SMILES: Cl[Sn]Cl.O.[I:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-])=O)=[CH:8][N:7]=1.[OH-].[Na+]>CCOC(C)=O>[I:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH2:13])=[CH:8][N:7]=1
Reactant: Cc1cc(I)ncc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(I)ncc1N
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a solution of SnCl2.H2O (20.5 g, 108 mmol) in EtOAc (200 mL) was added 2-iodo-4-methyl-5-nitropyridine (5.7 g, 21.6 mmol) in EtOAc (20 mL). Heat was released, and the reaction mixture was kept at reflux for 2 hr. After cooling to rt, the reaction mixture was treated with 50% NaOH (50 mL). Solid was filtered off and washed with EtOAc. The filtrate was washed with brine, dried, and concentrated to afford 2-iodo-4-methyl-5-pyridinamine (5 g, 99%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25]1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:24][CH:25]=3)=[O:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(O)c1c[nH]c2ccccc12
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1c[nH]c2ccccc12

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and indole-3-carboxylic acid were combined to provide N3-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-3-indolecarboxamide as a white powder, m.p. 225.5-227.4° C. 1H NMR (300 MHz, DMSO-d6) δ11.50 (broad s, 1H), 8.13 (d, J=7.9 Hz, 1H), 8.06 (d, J=10.2 Hz, 1H), 7.95-7.89 (m, 2H), 7.61 (d, J=8.3 Hz, 1H), 7.43-7.35 (m, 2H), 7.20-7.05 (m, 3H), 6.48 (broad s, 2H), 4.58 (t, J=7.2 Hz, 2H), 3.80 (t, J=6.6 Hz, 2H), 3.33 (m, 2H), 3.24-3.18 (m, 5H), 1.88 (m, 2H), 1.70 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ165.0, 152.0, 151.0, 145.1, 136.4, 132.6, 127.8, 126.8, 126.6, 126.4, 122.1, 121.5, 121.4, 120.6, 120.3, 115.1, 112.1, 111.0, 70.5, 58.4, 45.1, 38.2, 27.7, 27.5, 27.0; MS (EI) m/e 456.2282 (456.2274 calcd for C26H28N6O2).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:27]2[CH:28]=[C:29](OS(C(F)(F)F)(=O)=O)[CH:30]=[CH:31][CH:32]=2)([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:41][N:42](C=O)C>C(OCC)C.[C-]#N.[Zn+2].[C-]#N>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:26])=[CH:18][CH:19]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:41]#[N:42])[CH:28]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CCN(CC)C(=O)c1ccc(C2(c3cccc(OS(=O)(=O)C(F)(F)F)c3)CCCN(Cc3ccccc3)C2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccc(C2(c3cccc(C#N)c3)CCCN(Cc3ccccc3)C2)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-[1-benzyl-3-(4-diethylcarbamoyl-phenyl)-piperidin-3-yl]-phenyl ester (0.40 g, 0.69 mmol) in DMF (8 mL) was added zinc cyanide (0.057 g, 0.49 mmol) and tetrakis triphenylphosphine palladium (0.16 g, 0.14 mmol). The reaction was stirred under a nitrogen atmosphere at 90° C. for 5 hours. The mixture was cooled to room temperatures and it was diluted with diethyl ether (30 mL). The organic layer was washed with brine (5x 10 mL), dried (MgSO4) and concentrated. Purification with hexanes/EtOAc (1:1) afforded 0.28 g of 4-[1-benzyl-3-(3-cyano-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide. 1HNMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.69-7.20 (comp, 10H), 7.15-7.13 (comp, 2H) 3.60-3.38 (comp, 4H), 3.31-3.19 (comp, 2H), 3.09-2.94 (m, 1H), 2.58-2.45 (comp, 2H), 2.22-2.17 (comp, 3H), 1.71-1.61 (m, 1H), 1.28-1.16 (comp, 3H), 1.17-1.08 (comp, 3H); MS (M+1) 452.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11](=[O:15])OCC)=[N:2]1.[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:20]=[CH:21][C:22]=1[Cl:23].C1CCN2C(=NCCC2)CC1>CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11]([N:27]2[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=3)[CH2:29][CH2:28]2)=[O:15])=[N:2]1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CCOC(=O)Nc1n[nH]c2ccccc12
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Nc1n[nH]c2ccccc12)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 100 °C
Yield: 50.5 %

Procedure:
Ethyl 1H-indazol-3-ylcarbamate (250 mg), 1-(3,4-dichlorophenyl)piperazine (KANTO CHEMICAL CO. INC., 310 mg) and DBU (200 μl) were dissolved in dimethyl sulfoxide (4 ml), and the mixture was stirred with heating at 100° C. for 1 hr. By the work-up following the method of Example 12, 4-(3,4-dichlorophenyl)-1-piperazinecarboxylic acid (1H-indazol-3-yl)amide (240 mg, yield 50%) was obtained.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[C:20]([NH2:35])[CH:21]=[C:22]([NH:24][C:25]3[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[CH:23]=2)[CH:13]=1>C1COCC1>[CH3:8][NH:9][C:10]([NH:35][C:20]1[CH:21]=[C:22]([NH:24][C:25]2[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=2)[CH:23]=[C:18]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:19]=1)=[O:11]
Reactant: CN=C=O
Reactant: Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccnc2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccnc2)c1
Temperature: 40 °C

Procedure:
Triethylamine (44.2 μL, 0.317 mmol) followed by methyl isocyanate (18.1 mg, 0.317 mmol was added to a solution of 5-(pyridin-3-yl)-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzene-1,3-diamine (35 mg, 0.106 mmol) in THF (264 μL). The reaction mixture was heated to 40° C. for 4 hours, then cooled to room temperature and concentrated under reduced pressure. The solid was diluted with diethyl ether (5.00 mL) and was filtered to isolate 1-methyl-3-[3-(pyridin-3-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]urea as a tan powder. The product was further dried under reduced pressure. MS APC calc'd for C18H16F3N6O [M+H]+ 389. found 389. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.81 (s, 1H), 8.75 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 7.26 (s, 1H), 6.06 (s, 1H), 2.64 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH:18]([CH3:22])[CH2:17]3)=[CH:11][C:10]=2[F:23])=[N:6][CH:7]=1.N>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C@@H:16]3[CH2:21][CH2:20][NH:19][C@@H:18]([CH3:22])[CH2:17]3)=[CH:11][C:10]=2[F:23])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNC(C)C4)cc3F)ncc2Cl)n[nH]1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Nc2nc(Nc3cc(C)c([C@@H]4CCN[C@@H](C)C4)cc3F)ncc2Cl)n[nH]1

Procedure:
5-Chloro-N2-(2-fluoro-5-methyl-4-(2-methylpiperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (20 mg, 0.046 mmol) was dissolved in a solvent mixture of DCM and methanol (0.5 mL, 10/1 v/v+0.175N NH3). The mixture was applied to preparative TLC in order to separate the cis and trans stereoisomers (eluent: 6% MeOH in DCM with 0.1N NH3) of 5-Chloro-N2-(2-fluoro-5-methyl-4-(2-methylpiperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as white solids. The trans isomer was the preparative TLC top band and the cis isomer was the preparative TLC bottom band; ESMS m/z 430.1 (M+H+); cis stereoisomer 1H NMR (400 MHz, MeOD-d4): δ 8.03 (s, 1H), 7.84 (d, 1H), 7.02 (d, 1H), 6.24 (d, 1H), 3.90-3.85 (m, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 2.03-1.84 (m, 2H), 1.65-1.54 (m, 1H), 1.55 (d, 3H), 1.38-1.19 (m, 4H).