Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[C:11](=[O:24])[N:12](CC4C=CC(OC)=CC=4)[CH2:13][CH2:14][C:9]=3[C:8]([CH2:25][CH3:26])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.CS(O)(=O)=O.C(Cl)Cl>O>[CH:1]1([N:6]2[C:10]3[C:11](=[O:24])[NH:12][CH2:13][CH2:14][C:9]=3[C:8]([CH2:25][CH3:26])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(C2CCCC2)c2c1CCN(Cc1ccc(OC)cc1)C2=O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1nn(C2CCCC2)c2c1CCNC2=O
Temperature: 70 °C

Procedure:
The reaction mixture from Example 8 was cooled to 55° C. and slowly thereto trifluoroacetic acid (87.3 kg, 764 moles) was added while keeping the temperature between 50-60° C. The first ⅓ of the charge was exothermic and required external cooling. Methanesulfonic acid (6342 ml, 97.7 moles) was added and the reaction was warmed to ˜70° C. for two hours. The reaction was cooled to 20-25° C. and methylene chloride (17 gal, 64 L) was added followed by the slow addition of water (17 gal, 64 L). The layers were separated and the aqueous layer was diluted further with water (6 gal, 22.7 L) and then re-extracted with methylene chloride (6 gal, 22.7 L). The combined methylene chloride layers were mixed with water (29 gal, 110 L) and then brought to pH˜7.0 by the addition of saturated sodium bicarbonate (ca. 45 gal, 170 L). The layers were separated and the methylene chloride atmospherically distilled to about 9 gal (35 L). Ethyl acetate (13 gal, 49 L) was added and the reaction mixture was distilled to about 9 gal (35 L). The resulting slurry was cooled and granulated. The solids were collected by filtration, washed with ethyl acetate and vacuum dried at 40° C. under full vacuum. The yield was 7.91 kg, 71.2%; mp 152-153° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24]([SH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:24]([S:31][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: SCc1ccccc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Nc1nc(SCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, benzylmercaptan and DBU in DME. ES-MS m/e (%): 329 (M+H+, 100).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][C:12]#[N:13])=O>CO.O=[Pt]=O>[C:3]1(=[O:2])[NH:13][CH2:12][CH2:11][N:6]2[C:7](=[O:10])[CH2:8][CH:9]=[C:5]12
Reactant: COC(=O)C1CCC(=O)N1CC#N
Agent: O=[Pt]=O
Solvent: CO
Product: O=C1NCCN2C(=O)CC=C12
Yield: 63.1 %

Procedure:
1-Cyanomethyl-5-oxo-pyrrolidine-2-carboxylic acid methyl ester (1.1 g, 6.04 mmol) was dissolved in MeOH (30 ml) and hydrogenated over PtO2 (200 mg) at 20 psi for 24 hours. After filtration of the catalyst, the solvent was removed under vacuum and the residue triturated with iPrOH to afford the title compound as a white powder (580 mg, 62% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27])(=[O:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:24]([C:21](=[O:23])[CH3:22])[CH:25]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CC(=O)c1cccc(N)c1
Product: CC(=O)c1cccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c1
Yield: 87.7 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and m-acetylaniline (80 mg, 0.59 mmol) to give 200 mg of the title compound (85%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (bs, 1H), 10.23 (s, 1H), 8.12 (bs, 1H), 7.85 (d, 1H, J=8.1 Hz), 7.68 (d, 1H, J=8.1 Hz), 7.47 (t, 1H, J=8.1 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 5.18~5.28 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.55~2.70 (m, 2H), 2.56 (s, 3H), 2.12 (dm, 1H, J=13.5 Hz), 1.81~1.96 (m, 1H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:33][CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24]1>CN(C)C=O.O>[CH2:29]([O:28][C:26]([CH:25]1[CH2:31][CH2:32][CH2:33][N:23]([CH:16]2[CH2:17][N:14]([CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:15]2)[CH2:24]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C1CCCNC1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(C2CN(C(c3ccccc3)c3ccccc3)C2)C1
Temperature: 110 °C

Procedure:
Methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (A. G. Anderson, Jr. and R. Lok, J. Org. Chem., 1972, 37, 3953)(2.22 g, 7 mmol) and ethyl nipecotate (1.0 g, 6.37 mmol) were dissolved in dimethylformamide (3 mL) and heated at 110° C. for 1 hr. The mixture was cooled to ambient temperature, diluted with water and extracted with dichloromethane (3×15 mL). The extract was dried over anhydrous magnesium sulfate and the solvent removed under vacuum to give an impure sample of 1-(1-benzhydryl-azetidin-3-yl)-piperidine-3-carboxylic acid ethyl ester (2.91 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:21])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].O>O1CCCC1>[CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([OH:21])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1
Reactant: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Temperature: 25 °C

Procedure:
A solution of 1,3-dimethoxyestra-1,3,5(10)-trien-17-one (2.0 g, 6.4 mM) in 10 ml of anhydrous tetrahydrofuran is added dropwise to a well-stirred suspension of lithium tri-t-butoxyaluminum hydride (4.86 g, 19 mM) in 40 ml of anhydrous tetrahydrofuran at 0°. The suspension is maintained at 0° for 1 hr, warmed to 40° for 1/2 hr, cooled to room temperature and poured into 200 ml of cold H2O. The basic aqueous solution is extracted with 3 × 50 ml of ether and 3 × 50 ml of methylene chloride. The combined organic extracts are washed with H2O, dried over Na2SO4 and evaporated in vacuo to give an oily residue which is chromatographed on 100 g of neutral silica gel. Elution with chloroform gives 1,3-dimethoxy-17β-hydroxyestra-1,3,5(10)-triene, yield 1.9 g (95%); m.p. 53°-55° (hexane).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C-:11]#[N:12].[K+]>>[N:5]1[C:4]2[CH:8]=[CH:9][S:10][C:3]=2[C:2]([C:11]#[N:12])=[N:7][CH:6]=1
Reactant: Clc1ncnc2ccsc12
Reactant: [C-]#N
Agent: [K+]
Product: N#Cc1ncnc2ccsc12

Procedure:
Compound 6.2 is reacted with potassium cyanide according to a procedure in Miyashita, A. et. al. (Heterocycles 39, 1994, 345) to yield thieno[3,2-d]pyrimidine-4-carbonitrile (compound 7.1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:40])[CH:15]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[CH:19][C:18]=2[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].C(Cl)(Cl)Cl>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:40])[CH:15]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][C:18]=2[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OC(C(=O)NS(=O)(=O)c2ccc(C(C)C)cc2)c2ccc3c(c2)OCO3)c(CC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 60 °C
Yield: 82.7 %

Procedure:
To a solution of 0.294 g (0.52 mmol) of the product of Example 60 dissolved in 3.0 mL of methanol was added 1.0 mL of a 5.0 N aqueous solution of sodium hydroxide. The reaction mixture was magnetically stirred at 60° C. After 3 hours TLC analysis (CHCl3 --MeOH--NH4OH80:15:1) indicated complete hydrolysis of the ester. The reaction was cooled to room temperature, adjusted to pH=5 with dropwise addition of 1.0 N HCI, then partitioned between EtOAc and water. The organic layer was separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was dried in vacuo to afford 0.238 g (83%) of the title compound as an amorphous powder.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[O:9]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10]1.C([Si](C(C)C)(C(C)C)[O:21][CH2:22][C:23](=O)[CH2:24]O[Si](C(C)C)(C(C)C)C(C)C)(C)C.C(OC(=O)C)C>O1CCCC1>[OH:21][CH2:22][C:23]1[C:10]2[O:9][CH:13]=[CH:12][C:11]=2[C:14](=[O:16])[O:15][CH:24]=1
Reactant: O=C(O)c1ccoc1
Reactant: CC(C)[Si](OCC(=O)CO[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1occ(CO)c2occc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Add lithium diisopropylamine (0.454 mole) as a solution in tetrahydrofuran (100) mL to a solution of 3-furoic acid (23.36 g, 0.208 mole) at −78° C. over 30 minutes and stir for 1 hour at −78° C. To the resulting di-anion add 1,3-Bis-triisopropylsilanyloxy-propan-2-one as a solution in tetrahydrofuran (250 mL) over 30 minutes and stir at −78° C. for 1 hour and allow to warm to room temperature overnight. Quench the reaction with saturated aqueous ammonium chloride, pour into ethylacetate (1 L), add 1N HCL (1 L) and separate the two layers. Wash the organic layer with 1N HCl, water, and brine, dry over magnesium sulfate, filter and concentrate to an oil. Dissolve the crude oil in 50% tetrahydrofuran and 50% 3N HCl (1 L) and heat a reflux over night Distill off tetrahydrofuran, concentrate under reduced pressure and, add acetonitrile remove it under reduced pressure to azeotrope off the remaining water. Dissolve the resulting crude oil in acetonitrile (250 mL) and add the solution to a solution of toluene containing a catalytic amount of p-toluenesulfonic acid at reflux that is fitted with a Dean Stark trap over 30 minutes. Toluene was added to replace the acetonitrile and water removed by distillation and azetroping (500 mL). Heat the solution at reflux until it appears no further water is being removed. The hot solution was poured into an erlenmeyer flask and allowed to cool. Triturate the brown remaining residue with ethylacetate and methanol and combine it with the toluene solution and concentrate. Dilute with ethylacetate and wash with saturated aqueous sodium bicarbonate and brine, dry over magnesium sulfate and concentrate to an off white solid. Purification by flash chromatography eluting with hexane:ethylacetate gives 13.27 g (42%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12](CC3C=CC(OC)=CC=3)[S:11]2(=[O:27])=[O:26])[CH:3]=1.FC(F)(F)C(O)=O>ClCCl.CO>[CH3:15][C:13]1([CH3:16])[NH:12][S:11](=[O:27])(=[O:26])[N:10]([C:4]2[CH:3]=[C:2]([F:1])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH2:14]1
Reactant: COc1ccc(CN2C(C)(C)CN(c3cc(F)ccc3C#N)S2(=O)=O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CN(c2cc(F)ccc2C#N)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of 4-fluoro-2-(5-(4-methoxybenzyl)-4,4-dimethyl-1,1′-dioxido-1,2,5-thiadiazolidin-2-yl)benzonitrile (4.6 g, 11.81 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (2.73 mL, 35.4 mmol) and the mixture stirred at room temperature for 18 h. The mixture was diluted with methanol and the white solid collected by filtration and discarded. The cloudy solution was concentrated and the resulting solid was triturated with methanol and then filtered to give the title compound as a white solid (3.18 g, 100% yield). LCMS (M+H) calcd for C11H13FN3O2S: 270.07; found: 270.00. 1H NMR (300 MHz, CDCl3) δ: 7.66 (0.2H, dd, J=8.8, 5.8 Hz), 7.58 (1H, dd, J=9.5, 2.6 Hz), 7.10-7.04 (1H, m), 4.48 (1H, brs), 3.85 (2H, s), 1.55 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]Br>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([Br:31])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(O)c1ccc(F)c(Br)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(Br)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of EXAMPLE 412A (1.5 g, 6.8 mmol) and triphenyl phosphine (1.9 g, 7.2 mmol) in dimethylformamide (20 ml) was added bromine (1.1 g, 6.8 mmol) through a syringe. After the addition, the reaction mixture was stirred at room temperature for additional 15 minutes, and partitioned between water (100 ml) and ethyl acetate (200 ml). The organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (2.6% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH4) m/z 282 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[C:43]([O:48][C@H:49]([CH2:51][CH:52]=[CH2:53])[CH3:50])[C:42]=1B1OC(=O)CN(C)CC(=O)O1.C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=C(F)C(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C(C)=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:42]5[C:43]([O:48][C@H:49]([CH2:51][CH:52]=[CH2:53])[CH3:50])=[CH:44][CH:45]=[C:46]([F:47])[C:41]=5[F:40])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: C=CC[C@H](C)Oc1ccc(F)c(F)c1B1OC(=O)CN(C)CC(=O)O1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)c(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5c(O[C@@H](C)CC=C)ccc(F)c5F)c4)cn23)CC1
Yield: 45 %

Procedure:
Prepared from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate and (S)-2-(2,3-difluoro-6-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione in 45% yield following the same procedure as (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′,5′-difluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 716.7.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][NH2:9])[N:6]=1.[C:10](O)(=O)C.C=O>CO>[NH2:1][C:2]1[S:3][C:4]2[CH2:10][NH:9][CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: NCCc1csc(N)n1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: Nc1nc2c(s1)CNCC2
Yield: 91 %

Procedure:
A solution of 2-amino-4-(2-aminoethyl)thiazole (1.57 g, 11.0 mmol) in methanol (120 ml) was treated with acetic acid (0.15 ml, 2.6 mmol) and formaldehyde (0.89 ml of a 37% aqueous solution, 11 mmol). After ten minutes, the reaction mixture was concentrated in vacuo and subjected to column chromatography (eluant: 95:4:1 chloroform:methanol:concentrated ammonium hydroxide). The product was obtained as a white solid, m.p. 169°-173° (1.547 g, 10.0 mmol, 91% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([CH3:24])=[C:18]([O:25][CH3:26])[CH:17]=2)[N:3]=1.C1C(=O)N([Br:34])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([CH3:24])=[C:18]([O:25][CH3:26])[C:17]=2[Br:34])[N:3]=1
Reactant: COc1cc(Nc2nc(N)n(-c3ccc(C#N)cc3)n2)cc(OC)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Nc2nc(N)n(-c3ccc(C#N)cc3)n2)c(Br)c(OC)c1C
Yield: 42.4 %

Procedure:
To a suspension of 4-[5-Amino-3-(3,5-dimethoxy-4-methyl-phenylamino)-[1,2,4]triazol-1-yl]-benzonitrile (155 mg, 0.44 mmol) in CCl4 (10 mL) and benzene (10 mL) was added N-bromosuccimide (100 mg, 0.56 mmol) and benzoyl peroxide (10 mg). The reaction mixture was refluxed for 16 h. Concentration. The residue was purified by HPLC to give the title compound (80 mg). FIA-MS: m/e=429.1 and 431.1 (M+H), 427.1 and 429.1 (M−H). Rt=3.89 min (Method A). 1H-NMR (500 MHz, DMSO(d6)): 7.95 (d, 2H), 7.82 (s, 1H), 7.80 (d, 2H), 7.37 (s, 1H), 6.88 (br. s, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][N:3]=1.C1C=CC(OP(OC2C=CC=CC=2)([N:20]=[N+:21]=[N-:22])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.CCOC(C)=O>[N:20]([CH:8]([C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=1)[CH3:9])=[N+:21]=[N-:22]
Reactant: Cc1ncc(C(C)O)cn1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: Cc1ncc(C(C)N=[N+]=[N-])cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 1-(2-methylpyrimidin-5-yl)ethanol (2.48 g, 17 mmol) and diphenylphosphonic azide (9.3 mL, 41 mmol) in toluene (54.5 mL) at 0° C. was added neat 1,8-diazabicyclo[5.4.0]undec-7-ene (6.2 mL, 41 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then stirred at room temperature overnight. The mixture was diluted with EtOAc (100 mL) and washed with water (100 mL×2). The orangic layer was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH:5]1[CH2:8][CH:7]([N:9]2[CH2:15][C:14]3=[C:16]([C:34]#[N:35])[C:17]([Cl:33])=[CH:18][C:19]([CH:20]([N:22]4[C:26]5=[N:27][CH:28]=[N:29][C:30]([NH2:31])=[C:25]5[C:24]([CH3:32])=[N:23]4)[CH3:21])=[C:13]3[O:12][CH:11]([CH3:36])[CH2:10]2)[CH2:6]1.C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>CN(C)C=O>[NH2:31][C:30]1[N:29]=[CH:28][N:27]=[C:26]2[N:22]([CH:20]([C:19]3[C:13]4[O:12][CH:11]([CH3:36])[CH2:10][N:9]([CH:7]5[CH2:6][CH:5]([NH:4][C:44](=[O:46])[CH3:45])[CH2:8]5)[CH2:15][C:14]=4[C:16]([C:34]#[N:35])=[C:17]([Cl:33])[CH:18]=3)[CH3:21])[N:23]=[C:24]([CH3:32])[C:25]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CC(N)C2)C3)c2ncnc(N)c12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NC1CC(N2Cc3c(C#N)c(Cl)cc(C(C)n4nc(C)c5c(N)ncnc54)c3OC(C)C2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 4-(3-aminocyclobutyl)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile trishydrochloride was dissolved in N,N-dimethylformamide (2 mL) and triethylamine (10 μL, 0.1 mmol). To this mixture was added acetic anhydride (7.7 mg, 0.075 mmol). The reaction was stirred for 1 h at room temperature, and the reaction was purified without workup by prep HPLC on C-18 column eluting water:acetonitrile gradient buffered pH 10 to give two diastereomers: Peak #1 (Example 67): LCMS calculated for C25H30ClN8O2 (M+H)+: m/z=509.2; found: 509.2; Peak #2 (Example 68): LCMS calculated for C25H30ClN8O2 (M+H)+: m/z=509.2; found: 509.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([O:26]C)=[O:25])=[CH:15][C:13]=2[N:14]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc2nc(Nc3c(C)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Yield: 83.4 %

Procedure:
The title compound was prepared by following the procedure described for Step-2 of Intermediate-3 using methyl 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (0.500 g, 1.29 mmol), methanol (1.0 mL) and (50%) aqueous solution of sodium hydroxide (0.500 g, 12.50 mmol) to afford 0.400 g of the desired product. 1HNMR (DMSO-d6): δ 1.40 (s, 6H), 2.21 (s, 3H), 2.94 (s, 2H), 7.18-7.34 (m, 4H), 11.0-12.00 (s, 3H), 12-13.00 (s, 1H); MS [M+H]+: 372.34.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:3]1[CH2:14][OH:15].C([Sn](CCCC)=O)CCC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1(C)C=CC=CC=1>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[C@H:3]1[CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1COS(C)(=O)=O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A suspension of (2R,3S)-tert-butyl 3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5.04 g, 23.20 mmol) and dibutyloxostannane (7.07 g, 27.84 mmol) in toluene (50 mL) is refluxed in a 130° C. oil bath for 2 h. The mixture is cooled to 0° C. in an ice bath for 30 min and treated with methanesulfonyl chloride (2.15 mL, 27.84 mmol) at once. The reaction is stirred for 30 min at 0° C. and then the mixture allowed to gradually warm to ambient temperature overnight. The solution is concentrated and the resulting residue purified by medium pressure liquid chromatography, eluting with ethyl acetate:hexane (8:2). Fractions containing pure product are combined and concentrated to give 6.14 g (96%) of dense oil as the title compound. LC-ES/MS m/z 318.2 [M+Na]+, TR=2.34 min.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11]Br.[NH3:14]>CO>[Br:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:2])[NH:14][CH2:11]2
Reactant: N
Reactant: COC(=O)c1ccc(Br)cc1CBr
Solvent: CO
Product: O=C1NCc2cc(Br)ccc21
Temperature: 40 °C
Yield: 89 %

Procedure:
4-Bromo-2-bromomethylbenzoic acid methyl ester (0.70 g, 2.3 mmol) and sat. NH3 in MeOH (3 mL) were placed in a sealed tube. The mixture was heated at 40° C. overnight. After cooling to rt, the solids were collected to afford 5-bromoisoindolin-1-one (0.43 g, 89%). 1H NMR (DMSO-d6, 400 MHz) δ 8.62 (br s, 1H), 7.81 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 4.35 (s, 2H).