Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[CH:15]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:17])[CH3:16].[O-]CC.[Na+]>C(O)C>[Cl:14][C:11]1[CH:10]=[C:4]2[C:3]([CH2:2][N:22]([C:21]3[CH:23]=[CH:24][C:18]([CH:15]([CH3:17])[CH3:16])=[CH:19][CH:20]=3)[C:5]2=[O:7])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1cc(Cl)ccc1CBr
Reactant: CC(C)c1ccc(N)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1ccc(N2Cc3ccc(Cl)cc3C2=O)cc1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A mixture of ethyl 2-(bromomethyl)-5-chlorobenzoate (0.553 g, 1.99 mmol), 4-isopropylaniline (0.269 g, 1.99 mmol) and sodium ethoxide (0.406 g, 5.97 mmol) in ethanol (40 mL) was heated at reflux overnight. After this time, the mixture was cooled to room temperature and concentrated under vacuum. The mixture was partitioned between 1 N HCl and ethyl acetate. The organic layer was separated, washed with 1 N HCl, then with 1:1 water/brine solution, dried over sodium sulfate and filtered. Concentration under vacuum and recrystallization from ethyl acetate afforded 6-chloro-2-(4-isopropylphenyl)isoindolin-1-one (0.302 g, 53%) as an off-white solid: m.p. 206-209° C.; 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=1.9 Hz, 1H), 7.73 (dt, J=8.6, 2.7 Hz, 2H), 7.55 (dd, J=8.1, 1.9 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.30 (dt, J=8.5, 2.5 Hz, 2H), 4.83 (s, 2H), 2.96-2.90 (m, 1H), 1.26 (d, 6H); ESI MS m/z 286 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][CH:5]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[I-].[Na+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCl)cc1
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Temperature: 60 °C
Reaction time: 9 h

Procedure:
4-Chloromethylbenzoic acid methyl ester (1.66 g), 1-methylpiperazine (1.8 g) and sodium iodide (0.67 g) were added into acetone (50 ml). The reaction mixture was stirred at 60° C. for 9 hours. More 1-methylpiperazine (0.9 g) and sodium iodide (0.34 g) were added and after stirring additional 1½ hours at 60° C. the reaction mixture was allowed to cool into room temperature. The mixture was filtered and acetone was evaporated. The residue was dissolved in ethyl acetate and washed with water. The solvent was dried with NaSO4 and evaporated to yield 4-(4-methyl-piperazin-1-ylmethyl)benzoic acid methyl ester. 1H NMR (300 MHz, d6-DMSO) δ: 2.18 (s, 3H), 2.37 (bs, 8H), 3.53 (s, 2H), 3.84 (s, 3H), 7.44 (d, 2H, J 8.1 Hz), 7.91 (d, 2H, J 8.2 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[NH2:26])=[C:9]2[CH2:28][N:29]([S:33]([C:36]3[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=3)(=[O:35])=[O:34])[C:30]([CH3:32])([CH3:31])[C:8]2=[N:7]1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[N:53]1([C:59](Cl)=[O:60])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1.O1CCCC1>O>[CH2:1]([O:3][C:4]([N:6]1[C:10]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[NH:26][C:59]([N:53]2[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)=[O:60])=[C:9]2[CH2:28][N:29]([S:33]([C:36]3[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=3)(=[O:35])=[O:34])[C:30]([CH3:32])([CH3:31])[C:8]2=[N:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1N)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1NC(=O)N1CCOCC1)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Temperature: 60 °C
Reaction time: 168 h
Yield: 30.7 %

Procedure:
A mixture of 3-[2-Amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (308 mg, 0.5 mmol), N,N-diisopropylethylamine (0.104 mL, 0.6 mmol, 1.2 eq), morpholine-4-carbonyl chloride (1.2 mL, 10 mmol, 20 eq) and tetrahydrofuran (20 mL) was stirred at 60° C. for 7 days. The reaction mixture was then poured into water (100 mL), extracted with dichloromethane (100 mL), dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel (acetone as eluant) affording 112 mg of 5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-{4-(4-methyl-piperazin-1-yl)-2-[(morpholine-4-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester that was treated with 10 mL of methanol/triethylamine 8:2 and stirred at room temperature overnight. The mixture was evaporated to dryness and the residue purified by flash chromatography on silica gel using dichloromethane-methanol-30% NH4OH 96:4:0.4 as eluant, yielding the title compound as white solid (50 mg).
Reaction SMILES: [OH:1][C:2]1([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.[C:18](=O)(OCCCC)[O:19]CCCC.[Na].C(O)CCC>C1C=CC=CC=1>[CH:15]([N:14]1[CH2:13][C:2]2([CH2:8][O:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[O:4][CH2:3]2)[O:1][C:18]1=[O:19])([CH3:17])[CH3:16]
Reactant: CCCCOC(=O)OCCCC
Reactant: CC(C)NCC1(O)COc2ccccc2OC1
Agent: [Na]
Solvent: CCCCO
Solvent: c1ccccc1
Product: CC(C)N1CC2(COc3ccccc3OC2)OC1=O

Procedure:
A mixture of 3-hydroxy-3-isopropylaminomethyl-3,4-dihydro-2H-1,5-benzodioxepin (11.85 g.; 50 millimoles), prepared as described in Example 1, and dibutyl carbonate (13.1 g.) with a small piece of metallic sodium is heated in an oil bath. The temperature then is slowly raised to 170° C. with removal of butanol. Finally, the mixture is heated between 170°-200° C. with removal of excess dibutyl carbonate. The cooled reaction product is dissolved in benzene, washed with water, dried over sodium sulfate, and the solvent evaporated to give 3'-isopropyl-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-one, m.p. 121°-122° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[C:6](=O)[NH:5]2.P(Cl)(Cl)([Cl:24])=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[C:6]([Cl:24])=[N:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(Br)ccc2n2c(-c3ccccc3)nnc12
Solvent: CN(C)C=O
Product: Clc1nc2cc(Br)ccc2n2c(-c3ccccc3)nnc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
5z (197 mg, 0.58 mmol) was dissolved in DMF (3 mL) with heating, and then phosphorus oxychloride (0.27 mL, 2.9 mmol) was added, and the reaction was heated to 80° C. for 1.5 hours. After cooling to room temperature, the mixture was quenched with NaHCO3, and the resulting slurry was stirred at room temperature for 30 minutes and filtered. The solid material was washed with water and dried to obtain the desired product, 5aa.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)=C=O.CO.Cl.[Cl:17][C:18]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:19]=1[O:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].[C:33]([O:36][CH2:37]C)(=[O:35])C>N1C=CC=CC=1>[Cl:17][C:18]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:19]=1[O:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][S:10]([C:7]1[CH:8]=[CH:9][C:4]([NH:1][C:33](=[O:35])[O:36][CH3:37])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: CCOC(C)=O
Reactant: O=C=Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)Nc1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-isocyanatobenzenesulfonyl chloride (0.20 g, 0.92 mmol) in pyridine (0.92 mL) at 0° C. was added methanol (38 μL, 0.92 mmol). The ice bath was removed after 5 min, and the reaction mixture was slowly warmed to room temperature. After 1.5 hrs of stirring, 2-(2,4-dichloro-phenoxy)aniline hydrochloride (0.27 g, 0.92 mmol) was added. After 1.5 hrs of stirring, the reaction mixture was diluted with ethyl acetate and washed with 0.5 N HCl (×2), water (×2), half brine and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with 10-60% ethyl acetate in hexane to provide the title compound. MS (ES, M+H+): 467.0. 1H NMR (400 MHz, CD3OD) δ 7.62 (m, 3H), 7.48 (d, J=2.4 Hz, 1H), 7.43 (dd, J=9.2 Hz, 2H), 7.09 (m, 3H), 6.58 (m, 1H), 6.37 (d, J=8.8 Hz, 1H), 3.76 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:37]([N:40]1[CH:44]([C:45]2[CH:46]=[CH:47][C:48]([O:56][CH3:57])=[C:49]([CH:55]=2)[O:50][CH2:51][C:52](O)=[O:53])[CH2:43][C:42]([C:58]2[CH:63]=[C:62]([O:64][CH3:65])[C:61]([O:66][CH3:67])=[C:60]([O:68][CH3:69])[CH:59]=2)=[N:41]1)(=[O:39])[CH3:38]>ClCCl.O>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:52](=[O:53])[CH2:51][O:50][C:49]3[CH:55]=[C:45]([CH:44]4[N:40]([C:37](=[O:39])[CH3:38])[N:41]=[C:42]([C:58]5[CH:63]=[C:62]([O:64][CH3:65])[C:61]([O:66][CH3:67])=[C:60]([O:68][CH3:69])[CH:59]=5)[CH2:43]4)[CH:46]=[CH:47][C:48]=3[O:56][CH3:57])[S:10][C:6]=2[CH:5]=1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)Nc1nc2ccc(OC(F)(F)F)cc2s1
Yield: 787.1 %

Procedure:
To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetic acid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (10j) (531 mg, 80% yield).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:23]([C:34]([OH:36])=O)[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:37]CN=C=NCCCN(C)C.C1C=C[C:51]2[N:56]([OH:57])N=NC=2C=1.C(N(CC)CC)C.Cl.CN(C)O>C(Cl)Cl.CCOC(C)=O>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C@H:23]([C:34](=[O:36])[N:56]([O:57][CH3:37])[CH3:51])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)C[C@H]1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 53; 0.100 g, 0.204 mmol), EDCI (0.0548 g, 0.286 mmol) and HOBT (0.0359 g, 0.266 mmol) were mixed in CH2Cl2 (2.5 mL) and the mixture was cooled to 0° C. Triethylamine (0.0712 mL, 0.511 mmol) was added and the mixture was stirred for 15 minutes. Dimethyl hydroxylamine HCl (0.0299 g, 0.306 mmol) was added, and the mixture was warmed to ambient temperature and stirred for 4.5 hours. The mixture was diluted with EtOAc (20 mL) and washed with 1N KHSO4 (2×10 mL), followed by a saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography (1 to 5% MeOH/CH2Cl2) to provide 0.076 g (70%) of the product as a white foam.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[S:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C([O-])(=O)C.[K+]>CN(C)C(=O)C>[S:19]1[C:23]([C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:22][N:21]=[CH:20]1
Reactant: c1cscn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cncs3)ncnc21
Temperature: 200 °C
Yield: 63.8 %

Procedure:
4-Chloro-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 0.0106 mol), and 1,3-thiazole (7.50 mL, 0.106 mol) were dissolved in N,N-dimethylacetamide (40.0 mL). The solution was distributed in equal portions into four 20 mL microwavable vessels. Into each reaction vessel was then added potassium acetate (0.777 g, 7.93 mmol) followed by tetrakis(triphenyl-phosphine)palladium(0) (0.60 g, 2.1 mmol). Each reaction vessel was heated at 200° C. in the microwave reactor for 30 minutes. The reactions were combined and most of the solvent was removed in vacuo. The residue was diluted with DCM, filtered and concentrated. Purification by flash column chromatography (ethyl acetate/hexanes) afforded the desired product (2.25 g, 64%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23]([CH2:29][OH:30])=[C:24]([NH:26][CH2:27][CH3:28])[CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8]2=[O:32])[C:4]([CH3:33])=[N:3]1.[H-].[Na+].I[CH3:37]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23]([CH2:29][O:30][CH3:37])=[C:24]([NH:26][CH2:27][CH3:28])[CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8]2=[O:32])[C:4]([CH3:33])=[N:3]1
Reactant: CI
Reactant: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1COC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-8-(5-ethylamino-6-hydroxymethyl-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 155.1, 0.086 mmol) in DMF (0.5 ml) was treated with 55% NaH in oil (0.086 mmol) and the RM was stirred for 10 min at rt, then was added iodomethane (0.086 mmol) and the RM was stirred for 2 h at rt. The RM was quenched with water, diluted with DMF, filtered and purified by preparative HPLC. The pure fractions were basified with NaHCO3, concentrated and extracted with CH2Cl2 (3×) and with EtOAc. The combined organic layers were dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a film. (HPLC: tR 2.24 min (Method A); M+H=458 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.13-8.08 (m, 2H), 7.98-7.91 (m, 2H), 7.64-7.61 (m, 1H), 6.90 (s, 1H), 5.32 (t, 1H), 4.53 (s, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 3.28 (s, 3H), 3.20 (qt, 2H), 1.97 (s, 3H), 1.23 (t, 3H))
Reaction SMILES: [F:1][C:2]1[CH:3]=C([CH:7]=[C:8]([N:10]([CH3:17])[C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:9]=1)C#N.[OH-:18].[Na+].Cl.[CH2:21]([OH:23])[CH3:22]>CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:22]([CH:7]=[C:8]([N:10]([CH3:17])[C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:9]=1)[C:21]([OH:18])=[O:23]
Reactant: [OH-]
Reactant: CCO
Reactant: CN(c1cncnc1)c1cc(F)cc(C#N)c1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN(c1cncnc1)c1cc(F)cc(C(=O)O)c1
Yield: 91 %

Procedure:
Compound 12 (0.860 g, 3.77 mmol, 1.00 eq) was dissolved in ethanol (16 mL) and 1N NaOH (8 mL) was added. The mixture was refluxed for 18 h and after cooling the reaction was neutralized with 1N HCl (8 mL) and the reaction was concentrated in vacuo. The crude reaction was dissolved in 10% MeOH/CH2Cl2 and the undissolved salt was filtered off and the solvents were removed in vacuo to afford 0.852 g (91%) of the title compound as a pale-yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 8.65 (s, 2H), 7.35-7.32 (m, 1H), 7.26-7.18 (m, 2H), 3.36 (s, 3H); [M+1]+: 248.2.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[BH3-]C#N.[Na+]>CO>[O:16]1[CH2:17][CH2:18][N:13]([CH2:1][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])[CH2:14][CH2:15]1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(CN2CCOCC2)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 90579.6 %

Procedure:
To a solution of methyl 3-formylbenzoate (100 mg, 0.61 mmol) in MeOH (5 mL) was added morpholine (100 mg, 1.15 mmol) and the resulting mixture was stirred for 10 min at 20° C. To the mixture was added NaBH3CN (100 mg, 1.59 mmol) and the reaction mixture was stirred for 30 min at 20° C. The solution was concentrated and the residue was purified by prep-TLC to afford the title compound (130 g, Yield 90.9%). 1H NMR (CD3OD, 400 MHz): δ 7.98-8.05 (m, 1H), 7.92 (td, J=1.4, 7.7 Hz, 1H), 7.57-7.62 (m, 1H), 7.37-7.53 (m, 1H), 3.90 (s, 3H), 3.66-3.71 (m, 4H), 3.57 (s, 2H), 2.41-2.49 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([C@@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:12]([OH:16])[CH2:13][NH:14][CH3:15])[C:7]=12.[H][H]>C(O)C.[Pd]>[ClH:1].[ClH:1].[CH3:15][NH:14][CH2:13][C@@H:12]([OH:16])[C@H:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:8]1[C:7]2=[CH:2][N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9]1
Reactant: [H][H]
Reactant: CNC[C@@H](O)[C@H](c1ccccc1)n1ccc2ccnc(Cl)c21
Agent: [Pd]
Solvent: CCO
Product: CNC[C@@H](O)[C@H](c1ccccc1)n1ccc2ccncc21
Product: Cl

Procedure:
(1S,2R)-1-(7-chloro-pyrrolo[2,3-c]pyridine-1-yl)-3-methylamino-1-phenyl-propan-2-ol (0.12 g, 0.38 mmol) was dissolved in ethanol (20 mL) and treated with 10% palladium on carbon. The reaction mixture placed under 50 psi of hydrogen on a Parr shaker for 15 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo. The crude product was purified via Biotage Horizon (Flash 25 S, silica, gradient from 30% to 100% of 0.9% ammonium hydroxide in 10% methanol-methylene chloride/methylene chloride) to give a white solid as the free base of the expected product. The free base was dissolved in a minimum amount of ethanol and treated with a 1 N ethereal solution of hydrochloric acid until the solution was pH=3 followed by diethyl ether. The product was then crystallized by adding a minimum amount of ethyl acetate to afford the titled compound, (1S,2R)-3-methylamino-1-phenyl-1-(1H-pyrrolo[2,3-c]pyrid in-1-yl)-propan-2-ol dihydrochloride as a white solid. MS (ES) m/z 282.1.
Reaction SMILES: [O:1]1[C:22]2[C:5](=[CH:6][C:7]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9][C:8]=3[CH:21]=2)[NH:4][CH2:3][CH2:2]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(C(C)C)CC)(C)C.O>ClCCl>[CH3:23][S:24]([N:4]1[C:5]2=[CH:6][C:7]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH2:9][C:8]=3[CH:21]=[C:22]2[O:1][CH2:2][CH2:3]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)OCCN3
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(S(C)(=O)=O)CCO3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 130 mg of t-butyl 3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 4 ml of dichloromethane were added 0.036 ml of methanesulfonyl chloride and 0.089 ml of diisopropylethylamine under ice-cooling, followed by stirring at room temperature for 16 hours. To the reaction mixture were added 0.036 ml of methanesulfonyl chloride and 0.089 ml of diisopropylethylamine, followed by stirring at room temperature for additional 9 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 152 mg of t-butyl 4-(methylsulfonyl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a colorless solid.
Reaction SMILES: CS([C:5]1[N:14]2[C:8]([CH2:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1)(=O)=O.[O-:19][CH2:20][CH3:21].[Na+].C(O)C.C[O-].[Na+].CO>>[CH2:20]([O:19][C:5]1[N:14]2[C:8]([CH2:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1)[CH3:21]
Reactant: CC[O-]
Reactant: CS(=O)(=O)c1nnc2n1C=Cc1ccccc1C2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCOc1nnc2n1C=Cc1ccccc1C2

Procedure:
By a procedure similar to that described in Example 34, 3-methylsulfonyl-11H-s-triazolo[3,4-b][3] benzazepine was reacted with sodium ethoxide/ethanol, in lieu of sodium methoxide/methanol, to obtain 3-ethoxy-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from acetone yielded colorless needles, melting point: 143°-144° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([Br:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH2:28])[C:23]=1[I:29].[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:28][C:24]1[N:25]=[CH:26][N:27]=[C:22]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([Br:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[C:23]=1[I:29]
Reactant: C[C@H](N)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Reactant: Nc1ncnc(Cl)c1I
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1I)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Yield: 0 %

Procedure:
(S)-2-(1-Aminoethyl)-5-bromo-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (0.72 g, 2.16 mol) was treated with 6-chloro-5-iodopyrimidin-4-amine (1.55 g, 4.31 mol), cesium fluoride (0.66 g, 4.34 mol), N,N-diisopropylethylamine (1.88 mL, 10.79 mol) according to Preparation 13. The residue was purified using SP1® Purification System (0% to 70%, hexane-ethyl acetate) to give 0.39 g (32% yield) of the title compound as a solid. Purity 93%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[NH2:12][C:13](=[N:19]O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)C(C)C)(C)C.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[O:10][N:19]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1noc(Cc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
2-(4-chlorophenyl)acetyl chloride (0.554 mL; 3.78 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (15 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The formed precipitate was filtered off, suspended in pyridine (18 mL) and refluxed in a sealed tube for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.506 g (50%) of ethyl 5-(4-chlorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.