Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C)C.N12CCCNC1CCCC=C2.[CH3:16][C:17]1([CH3:29])[C:21]([CH3:23])([CH3:22])[O:20][B:19]([C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[O:18]1.[C:30]([CH:32]=[C:33]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1)#[N:31]>CCCCCCC>[C:30]([CH2:32][C:33]1([N:27]2[CH:28]=[C:24]([B:19]3[O:20][C:21]([CH3:22])([CH3:23])[C:17]([CH3:29])([CH3:16])[O:18]3)[CH:25]=[N:26]2)[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1)#[N:31]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: C1=CN2CCCNC2CCC1
Solvent: CC(C)O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a 1-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were sequentially added isopropanol (IPA, 200 mL), 1,8-diazabicyclo[5,4,0]undec-ene (DBU, 9.8 g, 64.4 mmol, 0.125 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 101 g, 520.51 mmol, 1.01 equiv) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 100 g, 514.85 mmol) at ambient temperature to generate a reaction mixture as a suspension. The resulting reaction mixture was heated to reflux in 30 minutes to provide a homogenous solution and the mixture was maintained at reflux for an additional 2-3 hours. After the reaction was complete as monitored by HPLC, n-heptane (400 mL) was gradually added to the reaction mixture in 45 minutes while maintaining the mixture at reflux. Solids were precipitated out during the n-heptane addition. Once n-heptane addition was complete, the mixture was gradually cooled to ambient temperature and stirred at ambient temperature for an additional 1 hour. The solids were collected by filtration, washed with n-heptane (200 mL), and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (3, 181 g, 199.9 g theoretical, 90.5%) as a white to pale yellow solid. For 3: 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.74 (s, 1H), 4.45-4.23 (m, 2H), 4.23-4.03 (m, 2H), 3.56 (s, 2H), 1.38 (s, 9H), 1.25 (s, 12H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 155.34, 145.50, 135.88, 116.88, 107.08 (br), 83.15, 79.36, 158.74 (br), 56.28, 27.96, 26.59, 24.63 ppm; C19H29BN4O4 (MW 388.27), LCMS (EI) m/e 389 (M++H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19](O)=[O:20])=[CH:16][CH:17]=2)[NH:12][N:11]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:25][CH:22]3[CH2:24][CH2:23]3)=[O:20])=[CH:16][CH:17]=2)[NH:12][N:11]=1
Reactant: O=C(O)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (200 mg, 0.719 mmol) in DMF (30 mL) was added cyclopropylamine (98 mg, 0.719 mmol), HATU (0.719 mmol, 273 mg), and triethylamine (0.726 mmol, 0.1 mL). This solution was allowed to stir at room temperature overnight. The reaction was worked up via aqueous wash and extraction with ethyl acetate (3×50 mL). The organic layer was then dried with MgSO4, filtered and concentrated to yield a dark oil. Flash column chromatography (3070% Ethyl Acetate/Petroleum Ether) afforded the 3-(1H-benzoimidazol-2-yl)-N-cyclopropyl-1H-indazole-6-carboxamide as a yellow solid. (0.130 g, 57%) 1H NMR (DMSO-d6) δ 13.88 (1H, s), 8.63 (1H, m), 8.51 (1H, d, J=85 Hz), 8.09 (1H, s), 7.75 (1H, d, J=8.7 Hz), 7.63 (2H, br s), 7.21 (2H, m), 2.89 (1H, m), 0.72 (2H, m), 0.63 (2H, m). MS (APCI positive) 318.1.
Reaction SMILES: Br[C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:26]=[O:27].Cl>O1CCCC1>[CH:26]([C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1)=[O:27]
Reactant: CC(C)(C)C(=O)Nc1cc(C(F)(F)F)c(Br)cn1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cc(C(F)(F)F)c(C=O)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Compound 6 (15.0 g, 46.2 mmol) was dissolved in 350 mL of anhydrous tetrahydrofuran and cooled to −78° C. under nitrogen. 45 mL of 2.5 M n-butyl lithium solution in tetrahydrofuran was slowly added to the reaction solution within one hour. The reaction solution was stirred at −78° C. for 1 hour, and then 15 mL of anhydrous N,N-dimethylformamide was slowly added dropwise and stirred for another 2.5 h at −78° C. To the reaction solution was added 120 mL of 1 M diluted hydrochloric acid to quench the reaction. The reaction mixture was extracted with ethyl acetate (200 mL×3). The organic layers were combined and washed with water (200 mL×3), saturated brine (200 mL) respectively, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography (petroleum ether: dichloromethane:ethyl acetate=60:10:1) to give 7.1 g of white solid (56.1%). m.p. 96-98° C. 1H NMR (300 MHz, CDCl3): δ 10.32 (br s, 1 H), 9.01 (s, 1 H), 8.73 (s, 1 H), 8.40 (s, 1 H), 1.38 (s, 9 H).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH2:14][N:15]2[CH:20]([CH3:21])[CH2:19][N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][C:16]2([C:29](=[O:31])[NH2:30])[CH3:28])[CH:6]=1.[OH-].[Na+].Cl>O1CCCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:32])=[O:2])=[CH:6][C:7]=1[O:12][CH2:13][CH2:14][N:15]1[CH:20]([CH3:21])[CH2:19][N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][C:16]1([C:29](=[O:31])[NH2:30])[CH3:28]
Reactant: COC(=O)Cc1ccc(Cl)c(OCCN2C(C)CN(c3ccccc3)CC2(C)C(N)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1CN(c2ccccc2)CC(C)(C(N)=O)N1CCOc1cc(CC(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.1 %

Procedure:
A mixture of [4-chloro-3-[2-(2,6-dimethyl-4-phenyl carbamoyl piperazine-1-yl)ethoxy]phenyl]acetic acid methyl ester (50 mg), 2N sodium hydroxide (0.1 mL) and tetrahydrofuran (1 mL) was stirred at room temperature for 4 hours. After neutralizing with 2N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel to give the title compound (18 mg). Yield: 37%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][OH:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[OH:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:25])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCO)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one and 6-methoxypyridine-3-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=1.269 min, m/z=432.2; 1H NMR (CDCl3) 1.50 (d, 3H), 2.05-2.35 (m, 5H), 2.90 (m, 1H), 3.51 (m, 1H), 3.70 (m, 1H), 3.97 (s, 3H), 5.63 (m, 1H), 6.85 (d, 1H), 6.92 (m, 2H), 7.17-7.35 (m, 6H), 7.81 (d, 1H), 8.32 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:22]([CH3:24])[CH3:23])[C:9](/[CH:18]=[CH:19]/[CH2:20][OH:21])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[CH3:27]I>CN(C)C=O>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:22]([CH3:24])[CH3:23])[C:9](/[CH:18]=[CH:19]/[CH2:20][O:21][CH3:27])=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)c1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1/C=C/CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC/C=C/c1c(C(C)C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.2 %

Procedure:
To a solution of (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propen-1-ol (30 mg) in N,N-dimethylformamide (1 mL) was added 60% sodium hydride in oil (3.8 mg) in an ice-water bath under nitrogen atmosphere. After 20 minutes, to the mixture was added methyl iodide (18.5 mg) at the temperature. After 15 minutes, the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate=10-1) to give 7-chloro-4-(4-fluorophenyl)-2-isopropyl-3-[(1E)-3-methoxy-1-propenyl]pyrrolo[1,2-b]pyridazine as a brown oil (3.5 mg, 10.2%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[N:3]=1.[CH2:13]([NH2:15])[CH3:14].[OH-].[Na+]>>[Cl:8][C:6]1[N:7]=[C:2]([NH:15][CH2:13][CH3:14])[N:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[N:5]=1
Reactant: CCN
Reactant: CC(C)Nc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Product: CCNc1nc(Cl)nc(NC(C)C)n1

Procedure:
In stage (b) the 2,4-dichloro-6-isopropylamino-s-triazine obtained in stage (a), ethylamine and sodium hydroxide, are reacted to produce 2-chloro-4-ethylamino-6-isopropylamino-s-triazine according to the scheme: ##STR4##
Reaction SMILES: C(O[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2([CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:14]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[ClH:36]>O1CCCC1.C(O)(C)C.O>[ClH:36].[CH3:4][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2([CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:14]1
Reactant: CCOC(=O)Nc1ccccc1N1CC2(CCN(C)CC2)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CNc1ccccc1N1CC2(CCN(C)CC2)c2ccccc21
Reaction time: 2 h

Procedure:
A solution of 2.26 g of 1-[2-(ethoxycarbonyl)aminophenyl]-1'-methylspiro[indoline-3,4'-piperidine] of Example 44 in 20 ml of dry tetrahydrofuran is added dropwise over 7 minutes to a rapidly stirred ice cold slurry of 0.94 g of lithium aluminum hydride in 10 ml of dry tetrahydrofuran under nitrogen. After heating at reflux for one hour, the reaction mixture is cooled in an ice bath and treated dropwise with 1 ml of water, 1 ml of 10% sodium hydroxide and 3 ml of water. The resultant salts are filtered and washed twice with hot chloroform. The filtrate is concentrated on a rotary evaporator and the residue is dissolved in chloroform, washed with brine, dried over anhydrous sodium sulfate, concentrated and pumped on under high vacuum to give the crude free base of the product. The free base is dissolved in 20 ml of isopropyl alcohol, cooled with an ice bath with stirring and treated dropwise with 50 ml of ethereal hydrogen chloride. The resulting clear solution is carefully concentrated to 15-20 ml and stored in a refrigerator for 2 hours, thus giving, after drying for 2 hours at 90° C. (under high vacuum), tiny needles, mp 266.5°-268.5° C., dec. Prolonged drying (24 hours) at 120° C. under high vacuum affords 1-[2-(N-methylamino)phenyl]-1'-methylspiro[indoline-3,4'-piperidine] hydrochloride, mp 271°-272° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[CH3:11][O-:12].[Na+].N1C=CC=NC=1.O>CO>[Cl:10][C:4]1[C:5]([Cl:9])=[C:6]([O:12][CH3:11])[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)c(Cl)c(Cl)n1
Agent: [Na+]
Solvent: c1cncnc1
Solvent: O
Solvent: CO
Product: COc1nc(C)nc(Cl)c1Cl

Procedure:
A solution containing 38 g (0.17 mol) of 2-methyl-4,5,6-trichloropyrimidine in 200 ml of methanol was cooled in an ice bath to 10`-15° C. and sodium methoxide as a 25 percent solution in methanol was added slowly with stirring until the starting pyrimidine could no longer be detected by GLC analysis. Water was then added and the resulting mixture was extracted with methylene chloride. Removal of the solvent and other volatiles from the extract by evaporation under reduced pressure left the title compound as a white powder melting at 77°-78° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]2[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([O:30]C)[CH:25]=3)=[CH:18][N:17]=2)[CH:6]=1)[CH3:3].[ClH:32]>C(O)C>[ClH:32].[ClH:32].[ClH:32].[ClH:32].[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]2[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([OH:30])[CH:25]=3)=[CH:18][N:17]=2)[CH:6]=1)[CH3:3]
Reactant: COc1cc(Cc2cnc(NCCSCc3cc(CN(C)C)ccn3)[nH]c2=O)ccn1
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1ccnc(CSCCNc2ncc(Cc3ccnc(O)c3)c(=O)[nH]2)c1

Procedure:
The product from Example 3, 2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone was heated under reflux in 2 N hydrogen chloride in ethanol to give 2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone tetrahydrochloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([CH2:19][C:20]#[N:21])[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.Cl>C1COCC1.CO>[CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([CH2:19][CH2:20][NH2:21])[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(CC#N)n3)ccc21
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(CCN)n3)ccc21

Procedure:
680 mg (2.19 mmol) of [4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]acetonitrile from step a are dissolved in 10 ml of THF, placed under nitrogen, boiled to reflux, and 1.21 ml (2.41 mmol) of a 2M borane dimethyl sulfide complex solution in THF are added. The mixture is refluxed for a further 40 min, cooled, a 1.25 M HCl solution in methanol is slowly added, the mixture is evaporated in a rotary evaporator. The residue is taken up in DCM, washed with a saturated sodium hydrogencarbonate solution. The organic phase is dried, filtered and evaporated. The brown oily residue is digested using a little ACN and filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34]([CH:36]3[CH2:38][CH2:37]3)=[O:35])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[CH:28]=3)[CH2:23][CH2:22]2)=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCC1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4Cl)CCCC3)CC2)c1)C1CC1

Procedure:
Example 119 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropane carboxamide according to the procedures described in Scheme 10: ESMS m/e: 526.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][NH2:5].S(=O)(=O)(O)[O-].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O.CN1CCOCC1>CN(C=O)C>[C:20]([O:19][C:17]([NH:5][CH2:4][C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[OH:1])=[O:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: NCc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-hydroxy-5-chlorobenzylamine (1.22 g, 4.77 mmol assuming the bisulfate salt), (BOC)2O (1.56 g, 7.16 mmol) and N-methylmorpholine (1.05 ml, 9.54 mmol) in DMF (10 ml) was stirred for 5 h at r.t. The reaction was partitioned between water and ethyl acetate and the organic layer was washed with 5% KHSO4 solution (2 times), sodium hydrogen carbonate solution and brine, dried (Na2SO4) and evaporated in vacuo to a solid. The crude product was recrystallized from ethyl acetate/hexanes (1:5, 12 ml) to give the title compound:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:15]3[NH:14][C:13]4[CH2:18][CH2:19][N:20]([C:22]5[N:27]=[CH:26][C:25]([C:28](OC)=[O:29])=[CH:24][N:23]=5)[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH2:4][CH2:3]1.C(Cl)Cl.[NH2:35][OH:36].[OH-].[Na+]>CO.O>[OH:36][NH:35][C:28]([C:25]1[CH:24]=[N:23][C:22]([N:20]2[CH2:19][CH2:18][C:13]3[NH:14][C:15]4[CH:16]=[CH:17][C:9]([CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:10][C:11]=4[C:12]=3[CH2:21]2)=[N:27][CH:26]=1)=[O:29]
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(CN5CCN(C)CC5)cc4c3C2)nc1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CN1CCN(Cc2ccc3[nH]c4c(c3c2)CN(c2ncc(C(=O)NO)cn2)CC4)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of methyl 2-{8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.1 g) in MeOH:DCM (5:2 mL) was added 50% aqueous hydroxylamine solution (2 mL) and to the mixture was added a solution of NaOH (0.08 g) in water (1 mL). The reaction mixture was stirred at room temperature for 1 hr and the progress of the reaction was monitored by TLC and upon completion of the reaction the solvent was removed under reduced pressure. The pH of the mixture was adjusted to 7.5 using 1N HCl and the obtained solid was filtered and washed with water followed by diethyl ether. After filtering, the solid was dried under vacuum to give N-hydroxy-2-{8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxamide (0.075 g). 1H NMR (DMSO-D6, 200 MHz) δ: 10.91 (2H, bm), 8.74 (2H, s), 7.64-7.01 (3H, m), 4.91 (2H, s), 4.19 (2H, s), 3.50-2.88 (10H, m), 2.87 (3H, s); m/e=422.9 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[CH:5](OC)[O:4][C@@H:3]1[CH2:10][O:11]/[N:12]=[C:13]1\[NH:14][C@@H:15]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=2)[CH2:16][C:17]2[N:18]=[C:19]([NH2:24])[N:20]=[C:21]([CH3:23])[C:22]\1=2.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C(Cl)Cl>[OH:1][C@H:2]1[C@@H:6]([OH:7])[CH2:5][O:4][C@@H:3]1[CH2:10][O:11]/[N:12]=[C:13]1\[NH:14][C@@H:15]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[N:33]=2)[CH2:16][C:17]2[N:18]=[C:19]([NH2:24])[N:20]=[C:21]([CH3:23])[C:22]\1=2
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OC[C@H]3OC(OC)[C@H](O)[C@@H]3O)N2)n1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OC[C@H]3OC[C@H](O)[C@@H]3O)N2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
To a solution of (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-((2R,3S,4R)-3,4-dihydroxy-5-methoxytetrahydrofuran-2-yl)methyl oxime (10.5 mg, 0.02 mmol) in CH2Cl2 (1 mL) was added Et3SiH (16 μL, 0.05 mmol) and BF3.Et2O (8.0 μL, 0.05 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred overnight at r.t. and poured on crushed ice. The resultant slurry was extracted with CH2Cl2 and washed with brine. Work-up and purification by Preparative LCMS afforded the title compound (3.0 mg, 30%) as light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.50 (s, 3H) 2.77 (dd, J=16.04, 6.95 Hz, 1H) 3.00 (dd, J=16.04, 5.18 Hz, 1H) 3.15-3.26 (m, 2H) 3.35-3.42 (m, 2H) 3.83 (s, 3H) 3.85-3.94 (m, 2H) 4.38-4.41 (m, 1H) 4.93-5.13 (m, 1H) 6.82 (d, J=9.09 Hz, 1H) 7.16 (d, J=7.07 Hz, 1H) 7.21-7.30 (m, 2H) 7.45 (dd, J=8.46, 5.94 Hz, 1H) 7.86 (dd, J=8.34, 7.33 Hz, 1H). MS (ES) [M+H] calculated for C25H28FN6O5, 511.51. found 511.20.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CS([O:11][CH2:12][C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:20][CH2:19]2)[S:16][CH:17]=1)(=O)=O.[CH3:30][C:31]1([CH3:44])[O:36][CH2:35][CH:34]([C:37]2[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=2)[CH2:33][O:32]1>CN(C=O)C>[CH3:30][C:31]1([CH3:44])[O:32][CH2:33][CH:34]([C:37]2[CH:42]=[CH:41][C:40]([O:11][CH2:12][C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]5[N:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[CH2:20][CH2:19]4)[S:16][CH:17]=3)=[CH:39][CH:38]=2)[CH2:35][O:36]1
Reactant: CS(=O)(=O)OCc1csc(C2CCN(c3ncccn3)CC2)n1
Reactant: CC1(C)OCC(c2ccc(O)cc2)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(c2ccc(OCc3csc(C4CCN(c5ncccn5)CC4)n3)cc2)CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 114.8 %

Procedure:
Cesium carbonate (735 mg, 0.0022 moles) was added to a solution of (2-(1-(pyrimidin-2-yl)piperidin-4-yl)thiazol-4-yl)methyl methanesulfonate (490 gm, 0.00112 moles) and 4-(2,2-dimethyl-1,3-dioxan-5-yl)phenol (281 mg, 0.001384 moles) in DMF (10 ml) and the reaction mixture was stirred at 60° C. for 2 hours. Then the reaction mixture was then poured into ice cold water and extracted with ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product so obtained was purified by column chromatography (silica gel) using 22% ethyl acetate in hexane as eluent to obtain 600 mg product as white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)[C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2.[F:28][C:29]([F:36])([C:32]([F:35])([F:34])[F:33])[CH2:30][NH2:31]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([NH:31][CH2:30][C:29]([F:36])([F:28])[C:32]([F:35])([F:34])[F:33])=[O:18])[C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2
Reactant: NCC(F)(F)C(F)(F)F
Reactant: COCCN1C(=O)[C@@H](NC(=O)CC(=O)O)c2ccccc2-c2ccccc21
Product: COCCN1C(=O)[C@@H](NC(=O)CC(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using N—[(S)-5-(2-methoxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. White solid (80%). MS: m/e=500(M+H+).