Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[CH2:12][N:11]([CH2:23][CH2:24][O:25][CH3:26])[C:10]1=[O:27].C1C([N+]([O-])=O)=CC=C([Cl-][C:38]([O-])=[O:39])C=1.Cl.Cl.[O:43]=[C:44]1[NH:52][C:47]2=[N:48][CH:49]=[CH:50][CH:51]=[C:46]2[N:45]1[CH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[CH:13]1[CH2:12][N:11]([CH2:23][CH2:24][O:25][CH3:26])[C:10](=[O:27])[CH:9]([NH:8][C:38]([N:56]2[CH2:57][CH2:58][CH:53]([N:45]3[C:46]4[C:47](=[N:48][CH:49]=[CH:50][CH:51]=4)[NH:52][C:44]3=[O:43])[CH2:54][CH2:55]2)=[O:39])[CH2:14]1
Reactant: COCCN1CC(c2cccc(F)c2F)CC(N)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCN1CC(c2cccc(F)c2F)CC(NC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
Triethylamine (83 μL, 0.598 mmol) was added to a solution of 3-amino-5-(2,3-difluorophenyl)-1-(2-methoxyethyl)piperidin-2-one (170 mg, 0.598 mmol) and 4-nitrophenylchloroformate (121 mg, 0.598 mmol) in tetrahydrofuran (4 mL) at 0° C. After 1 h, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (174 mg, 0.651 mmol), triethylamine (249 μL, 1.794 mmol) were added and the mixture allowed to warm to ambient temperature. After 18 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/5% (10% ammonium hydroxide/methanol)] gave the title compound (0.135 g). MS 529.2353 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.03 (dd, J=5.3, 1.1 Hz, 1H), 7.38 (dd, J=7.8, 1.2 Hz, 1H), 7.11-7.03 (m, 2H), 7.01-6.96 (m, 2H), 5.82 (d, J=3.4 Hz, 1H), 4.58-4.53 (m, 1H), 4.34-4.30 (m, 1H), 4.23 (d, J=6.6 Hz, 2H), 3.71-3.62 (m, 3H), 3.60-3.53 (m, 3H), 3.52-3.46 (m, 1H), 3.33 (s, 3H), 2.96 (dd, J=23.4, 10.5 Hz, 2H), 2.80-2.78 (m, 1H), 2.28-2.21 (m, 2H), 1.90 (dd, J=10.5, 2.0 Hz, 2H).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]([CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[OH:13].CN(C)C=O>C1C=CC=CC=1>[CH3:20][N:17]1[CH2:18][CH2:19][CH:14]([CH:12]2[C:8]3=[CH:9][CH:10]=[CH:11][N:7]3[CH2:6][C:5]3[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=3[O:13]2)[CH2:15][CH2:16]1
Reactant: CN1CCC(C(O)c2cccn2Cc2ccccc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CN1CCC(C2Oc3ccccc3Cn3cccc32)CC1

Procedure:
To a suspension of sodium hydride (2.0 g, 50% in oil, treated with hexanes, 0.04 mole) in 50 ml benzene was added a suspension of [1-(2-fluorobenzyl)-2-pyrryl]-[(1-methyl)piperidin-4-yl]methanol (10.0 g, 0.033 mole) in 100 ml benzene, followed by 50 ml dimethylformamide.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21]C)=[N:10][C:9]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])=[N:10][C:9]=1[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(NC(=O)c3ccccc3OC)sc2Cc2ccccc2)cc1
Agent: BrB(Br)Br
Product: O=C(Nc1nc(-c2ccc(O)cc2)c(Cc2ccccc2)s1)c1ccccc1O
Yield: 64.4 %

Procedure:
A procedure similar to that in Example 7 was used. N-[5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-2-methyoxy-benzamide prepared in Example 36 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone to give a product as a white solid in a yield of 64.4%, mp: 279-280 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 4.19 (2H, s, CH2), 6.85 (2H, d, J=8.40 Hz, ArH), 6.94˜7.02 (2H, m, ArH), 7.22˜7.28 (3H, m, ArH), 7.34 (2H, t, J=7.84 Hz, ArH), 7.42˜7.48 (3H, m, ArH), 7.96 (1H, d, J=7.84 Hz, ArH), 9.70 (1H, br, OH), 12.15 (1H, br, CONH); EI-MS m/e (%): 402.2 (M+, 63), 282.1 (100); HREI-MS Calcd. for C23H18N2O3S: 402.1038. found: 402.1037. Anal. Calcd. for C23H18N2O3S: C, 68.64; H, 4.51; N, 6.96. found: C, 68.45; H, 4.38; N, 6.80.
Reaction SMILES: C([S:9][CH:10]([CH3:19])[C:11]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12])(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>O>[SH:9][CH:10]([CH3:19])[C:11]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(SC(=O)c1ccccc1)C(=O)NCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(S)C(=O)NCCC(=O)O
Reaction time: 1 h

Procedure:
22.5g (0.08 mol) of N-(2-benzoylmercaptopropionyl-β-alanine was added to the solution of 10.0g (0.25 mol) of NaOH in 100 ml of water to allow the β-alanine derivative to hydrolyze at 40°C for 1 hour. The reaction mixture was acidified with hydrochloric acid and, after distilling off the benzoic acid, concentrated to give 8.8g of N-(2-mercaptopropionyl-βalanine, ##EQU11##
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[C:16]2=[CH:17][N:18]=[C:19]([CH:20]3[CH2:23][C:22](=[O:24])[CH2:21]3)[N:15]2[N:14]=[CH:13][N:12]=1>CN(C=O)C>[Br:8][C:17]1[N:18]=[C:19]([CH:20]2[CH2:23][C:22](=[O:24])[CH2:21]2)[N:15]2[C:16]=1[C:11]([O:10][CH3:9])=[N:12][CH:13]=[N:14]2
Reactant: COc1ncnn2c(C3CC(=O)C3)ncc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COc1ncnn2c(C3CC(=O)C3)nc(Br)c12

Procedure:
NBS (2.00 g, 0.01 mol) was added in one portion to a stirred, cooled solution of 3-(4-methoxyimidazo[5,1-f][1,2,4]triazin-7-yl)cyclobutanone (6.0 g, 0.027 mol) in DMF (40 mL) at 0° C. under N2. Two other portions of NBS (2.00 g, 0.01 mol) were added after 15 and 30 min respectively. The reaction was stirred with cooling for 5 h. The reaction mixture was partitioned between EtOAc (1 L) and brine (200 mL) and then 83 of 219 organic layer was washed with brine (2×150 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using hexanes:EtOAc (1:1) as the eluent. 1H NMR (400 MHz, Chloroform-d) δ 3.45-3.60 (m, 3H), 3.66-3.77 (m, 2H), 4.19 (s, 3H), 8.01 (s, 1H).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:15])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:15][C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1]([OH:11])=[CH:2][CH:3]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(Cl)c2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
A solution of 37 grams (0.25 mole) of 5,6,7,8-tetrahydronaphthol in 200 ml of carbon tetrachloride was treated dropwise with stirring with 33.8 grams (0.25 mole) of sulfuryl chloride at room temperature. When addition was complete the reaction mixture slowly brought to boiling over a 1 hour period and held there at reflux for 30 minutes. After cooling to ambient temperature the reaction mixture was washed with 10 percent aqueous sodium carbonate and then with water. After drying over calcium chloride the carbon tetrachloride solution was distilled to give a portion, b.p. 110-112/0.25 mm, which was recrystallized from hexane to give 8 grams (17.5 percent) of product, m.p. 58°-59°C.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=2[C:20](OC)=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:21][CH2:20][C:8]1[CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:11][CH2:12][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1=C(c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)=C(CO)C1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a solution of 1-tert-butyl 3-methyl 4-phenyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate (740 mg, 2.33 mmol) in THF (7.2 mL) was added 1M LiAlH4 in THF (2.80 mL, 2.80 mmol) at −20° C. dropwise, after stirring at −20° C. for 30 min, it was quenched with Sat. NH4Cl, the mixture was extracted with EtOAc. Organic layers were combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=60:40) to give tert-butyl 5-(hydroxymethyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (512 mg).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].CS(O[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1)(C)(C)C>ClCCl.CO>[C:31]([O:30][C:28](=[O:29])[NH:27][CH:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][C:2]2=[O:11])[CH2:22][CH2:23]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: O=c1ccc2ccccc2[nH]1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccccc32)CC1
Yield: 34.8 %

Procedure:
Quinolin-2(1H)-one (250 mg, 1.7 mmol) was deprotonated with sodium hydride (60% in oil, 70 mg, 1.7 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (1.7 mmol) as described for Intermediate 141. Chromatography on silica gel with 0-5% methanol in dichloromethane gave 220 mg (35%) of product as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21]C)=[O:20])[CH:17]=3)[N:12]=[C:11]([N:23]3[CH2:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[S:26](=[O:35])(=[O:34])[CH2:25][CH2:24]3)[CH:10]=2)[CH2:6][O:5][CH2:4]1.[OH-].[Na+]>O1CCCC1.O>[NH2:1][CH2:2][C:3]1([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=3)[N:12]=[C:11]([N:23]3[CH2:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[S:26](=[O:35])(=[O:34])[CH2:25][CH2:24]3)[CH:10]=2)[CH2:4][O:5][CH2:6]1
Reactant: COC(=O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(CN)COC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(C(=O)O)cc23)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
To a stirred solution of methyl 4-({[3-(aminomethyl)oxetan-3-yl]methyl}amino)-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate (100 mg, 0.2 mmol) in tetrahydrofuran and water (4 mL, V/V=3/1) was added sodium hydroxide (40 mg, 1.0 mmol). After being stirred at room temperature overnight, the resulting mixture was concentrated in vacuo to remove the organic solvent. The residual aqueous solution was acidified with an aqueous solution of citric acid (5 mL, 20%) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a sticky solid, which was purified by flash column chromatography (eluting with 5% methanol in dichloromethane) to afford 20 mg of the desire product as a solid. MS obsd. (ESI+) [(M+H)+] 483, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (s, 1 H), 8.01 (d, 1 H), 7.90 (m, 2 H), 7.61 (t, 1 H), 7.47 (t, 1 H), 7.32 (d, 1 H), 6.29 (s, 1 H), 5.76 (s, 2 H), 4.40 (m, 6 H), 3.78 (s, 2 H), 3.62 (s, 2 H), 3.17 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42]>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[C:37](=[O:42])[CH2:38]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: CN1CCNCC1=O
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)C(=O)C4)c(OC)cc23)c2c1OCO2
Yield: 71.3 %

Procedure:
This was prepared by the method described in example 13 using N-[5-Chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (200 mg, 0.40 mmol) and 1-methylpiperazin-2-one (226 mg, 1.98 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (166 mg, 72%) as a pale brown solid; NMR Spectrum:(CDCl3) 2.10 (quintet, 2H), 2.61 (t,2H), 2.72 (m, 4H), 2.95 (s, 3H), 3.15 (s, 2H), 3.31 (t, 2H), 3.40 (s, 3H), 3.61 (t, 2H), 3.98 (s, 3H), 4.25 (t, 2H), 6.06 (s, 2H), 6.96 (s, 1H), 7.03 (s, 1H), 7.12 (s, 1H), 7.26 (s, 1H), 8.60 (s, 1H); Mass Spectrum: M+H+ 582/584.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:22]=[C:23]([S:28]([CH2:31][CH2:32][OH:33])(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:21]2[CH:22]=[C:23]([S:28]([CH2:31][CH2:32][OH:33])(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=2[CH3:27])[CH:11]=1)#[N:16]
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1Br
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)CCO)cc1C#Cc1cc(C#N)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 2-[(3-bromo-4-methylphenyl)sulfonyl]ethanol (Intermediate 67), the title compound was obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][O:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[C:13]([CH2:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[C:9]=2[C:8](=[O:33])[N:7]([CH2:34][CH2:35]O)[C:6]1=[O:37].[NH:43]1[CH:47]=[N:46][N:45]=[N:44]1>>[F:42][C:38]1[CH:39]=[CH:40][CH:41]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][O:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[C:13]([CH2:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[C:9]=2[C:8](=[O:33])[N:7]([CH2:34][CH2:35][N:43]2[CH:47]=[N:46][N:45]=[N:44]2)[C:6]1=[O:37]
Reactant: COCCN(C)Cc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(CCO)c(=O)n2Cc1c(F)cccc1F
Reactant: c1nnn[nH]1
Product: COCCN(C)Cc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(CCn1cnnn1)c(=O)n2Cc1c(F)cccc1F

Procedure:
The similar reaction as described in Example 6 by using the compound obtained in Example 8 (250 mg, 0.414 mmol) and tetrazole (145 mg, 2.07 mmol) gave the title compound 2-yl form (66 mg, 24%) and 1-yl form (27 mg, 10%) as white amorphous compounds.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22].[F:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=O>>[Br:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[C:26]([C:25]3[C:24]([F:23])=[N:32][CH:31]=[CH:30][CH:29]=3)[N:22]=[C:16]2[CH:17]=1
Reactant: O=C(Cl)c1cccnc1F
Reactant: Nc1cc(Br)cc[n+]1N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Fc1ncccc1-c1nc2cc(Br)ccn2n1
Yield: 70.7 %

Procedure:
The product was prepared in the same manner as described in example 1b using 1,2-diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (2.2 g, 5.67 mmol) and 2-fluoronicotinoyl chloride (1.81 ml, 11.3 mmol) as starting materials. The reaction affords 7-bromo-2-(2-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.175 g, 70.8%) as light brown solid. MS: m/z=294.9 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH2:5][C:4]([CH3:20])([CH3:19])[NH:3]1.[CH:22]1([C:25]2[C:30]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:29][C:28]([NH2:36])=[C:27]([F:37])[CH:26]=2)[CH2:24][CH2:23]1>CC(O)C>[CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]([NH:36][C:28]3[CH:29]=[C:30]([N:31]4[CH:35]=[N:34][N:33]=[N:32]4)[C:25]([CH:22]4[CH2:23][CH2:24]4)=[CH:26][C:27]=3[F:37])[N:10]=2)[CH2:5][C:4]([CH3:20])([CH3:19])[NH:3]1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2C(N)=O)CC(C)(C)N1
Reactant: Nc1cc(-n2cnnn2)c(C2CC2)cc1F
Solvent: CC(C)O
Product: CC1(C)CC(Nc2nc(Nc3cc(-n4cnnn4)c(C4CC4)cc3F)ncc2C(N)=O)CC(C)(C)N1
Temperature: 100 °C
Yield: 45.4 %

Procedure:
A mixture of 4-(2,2,6,6-tetramethylpiperidin-4-ylamino)-2-chloropyrimidine-5-carboxamide (178 mg, 0.570 mmol, 1 equiv), 4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)benzenamine (150 mg, 0.684 mmol, 1.2 equiv), and PTSA monohydrate (230 mg, 1.20 mmol, 2.1 equiv) in IPA (6 mL) were heated to 100° C. overnight giving a precipitate. The precipitate was collected by vacuum filtration and rinsed with IPA. The solid was taken in EtOAc then adjusted to ca. pH 12-14 with 1N NaOH. The aqueous and organic layers were partitioned. The aqueous layer was extracted with EtOAc (2×150 mL). The combined organics were washed with 1N NaOH (1×150 mL), dried (Na2SO4), filtered, and concentrated to give the desired product (128 mg, 50%) as a solid.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[BrH:12].BrBr.N([O-])=O.[Na+].[OH-].[Na+]>O.C(OCC)(=O)C>[Br:12][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Br
Reactant: CC(C)(C)c1ccnc(N)c1
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccnc(Br)c1
Yield: 85 %

Procedure:
39.0 g (0.26 mol) of 2-amino-4-tert-butyl-pyridine was added with ˜100 mL of 60% HBr, then stirred at −10° C. to −17° C. 124.0 g (0.78 mol) of pre-cooled Br2 (˜0° C.) was added dropwise added and the mixture was stirred for 20 mins. Pre-cooled (0° C.) NaNO2 solution of 46.0 g (0.67 mol) of NaNO2 dissolved in ˜80 mL of water was added dropwise into the reaction mixture at −10° C. to −17° C. After addition, the reaction was stirred for one hour. Ice-cooled ˜25% NaOH solution was added slowly until the solution became basic. 200 mL of ethyl acetate was added to the mixture to extract the organic phase. The organic phase solvent was evaporated and distilled under vacuum. ˜47 g (85% yield) of 2-bromo-4-tert-butyl-pyridine was obtained. The product was confirmed by MS.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.O.[NH2:35][NH2:36].C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:35][NH:36]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: C[C@@H]1CO[C@H](CNC(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@@H]1CO[C@H](CNC(=O)c2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 44.6 %

Procedure:
A mixture of crude N-({(2R,5R)-4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methyl)benzamide (0.23 mmol theoretical) and hydrazine monohydrate (0.25 mL, 5.14 mmol) in ethanol (3 mL) was stirred at 100° C. in a sealed tube for 15 hours. The mixture was cooled, poured into saturated aqueous NaHCO3 (15 mL), and extracted with EtOAc (2×10 mL). The extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified on a Gilson reverse phase HPLC (CH3CN/water with 0.1% TFA). The product fractions were concentrated in vacuo, taken up in a small amount of CH3OH, and added to saturated aqueous NaHCO3 (25 mL). That mixture was extracted with 90/10 CH2Cl2/IPA (3×25 mL), and the extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (47 mg) as a pale yellow solid. LC-MS (ES) m/z=459 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.19 (d, J=6.8 Hz, 3H), 2.73-2.91 (m, 1H), 3.39-3.55 (m, 2H), 3.57-3.71 (m, 2H), 3.73-3.83 (m, 1H), 4.08-4.74 (bs, 2H), 5.39 (s, 2H), 6.14 (s, 2H), 6.57 (s, 1H), 7.45-7.51 (m, 2H), 7.51-7.60 (m, 2H), 7.72 (d, J=8.6 Hz, 1H), 7.90 (d, J=7.6 Hz, 2H), 7.95 (s, 1H), 8.68 (t, J=5.5 Hz, 1H), 11.53 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][C:15](=[O:19])[NH:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35].C([O-])(O)=O.[Na+]>CC(O)C.C(Cl)(Cl)Cl>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][C:15](=[O:19])[NH:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1)=[O:35]
Reactant: NC1CCN(Cc2ccc3c(c2)NC(=O)CC3)CC1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)NC2CCN(Cc3ccc4c(c3)NC(=O)CC4)CC2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a CHCl3 (5.00 mL) solution of the compound (250 mg) obtained in Step 1-6, iPr2NEt (370 μL) and 3-methoxybenzoyl chloride (180 mg) were added and the mixture was stirred at room temperature for three days. To the reaction mixture, a saturated aqueous NaHCO3 solution was added and the solution was extracted with CHCl3 four times. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography [(silica gel 60 N, mobile phase: MeOH/CHCl3=0/100 to 10/90; v/v) and (Chromatorex NH, mobile phase: CHCl3) in this order] to obtain a solid. To the solid obtained, IPA was added at room temperature and the mixture was stirred for one hour, filtrated and washed with IPA and hexane to obtain the titled compound (159 mg, a colorless solid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[C:9]2=[O:16])=[CH:4][CH:3]=1.CO.[CH2:19]1COCC1.[N+](=C[Si](C)(C)C)=[N-]>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH3:19])=[O:14])[C:9]2=[O:16])=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Reactant: C1CCOC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CCN(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.20 g, 0.90 mmol) in a mixture of Et2O (6 mL), MeOH (2 mL), and THF (2 mL) was added (diazomethyl)trimethylsilane (1.1 mL, 2.0 M) at 0° C. The resulting mixture was stirred for 30 minutes at room temperature, quenched with AcOH, and diluted with EtOAc. The organic layer was washed with water, NaHCO3 solution (2×), and brine, dried over MgSO4, and concentrated under reduced pressure to give the desired product (0.206 g, 98%). LRMS (ESI pos) m/e 238.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:12]([CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:14](=[O:16])[CH3:15])[CH:3]=2)[NH:7][CH:6]=1)#[N:13]
Reactant: CC(=O)OC(C)=O
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2[nH]cc(CC#N)c2c1
Reaction time: 18 h

Procedure:
A solution of 6.0 g (0.035 mole) of 5-aminoindole-3-acetonitrile, Example 1, in 30 ml pyridine was treated with 15 ml of acetic anhydride. After stirring 18 hours, the solvent was removed in vacuo and residue recrystallized twice from EtOH to yield 4.35 g of product: m.p. 176°-177°.