Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[CH:10]=[N:11][NH:12][C:13]=1[CH3:14])=[O:6])([CH3:4])[CH3:3].[CH3:15][Mg+].[Br-]>C1COCC1>[CH3:4][C:2]([S:5]([NH:7][CH:8]([C:9]1[CH:10]=[N:11][NH:12][C:13]=1[CH3:14])[CH3:15])=[O:6])([CH3:1])[CH3:3]
Reactant: Cc1[nH]ncc1/C=N/S(=O)C(C)(C)C
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1[nH]ncc1C(C)NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-2-methyl-N-((5-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide (Step A9B) (2.1 g, 9.29 mmol) in THF (45 ml) was added a 1M solution of MeMgBr in THF (27.9 ml, 27.9 mmol) at −48° C. under nitrogen. After being stirred for 60 min, the reaction mixture was allowed to warm to rt and then heated at 90° C. for 4 hours.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[N:17]=[CH:18][S:19][CH:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[CH:34][C:33]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[N:17]=[CH:18][S:19][CH:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2cscn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CN(c2cscn2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nccc3c2)cc1
Temperature: 125 °C

Procedure:
To a solution of 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)isoquinoline-6-sulfonamide (0.10 g, 0.224 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (0.064 g, 0.292 mmol) and cesium carbonate (0.292 g, 0.897 mmol) in DME (2.437 ml) and Water (0.366 ml) was added Pd(PPh3)4 (0.026 g, 0.022 mmol) in one portion. The resulting mixture was heated to 125° C. in the microwave for 2 hours. The resulting mixture was transferred to a seperatory funnel and the aqueous layer was washed 3× with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The crude mixture was purified by the silica gel chromatography (100% hexanes to 25% EtOAc in hexanes to 90% EtOAc in heptanes). m/z (ESI) 586.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[N:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=1[CH2:35]Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+]>CN(C=O)C.C(OCC)C>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=1[CH2:35][N:8]([C:9]1[N:14]=[N:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)nn1
Reactant: BrCc1cc(Br)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(N(Cc2cc(Br)ccc2OCc2ccccc2)C(=O)OC(C)(C)C)nn1
Reaction time: 2 h

Procedure:
A mixture of ethyl 6-(tert-butoxycarbonylamino)-3-pyridazine carboxylate (2.4 g), 1-(benzyloxy)-2-bromomethyl-4-bromobenzene (3.2 g) and sodium hydride (0.5 g of a 50% W/W dispersion in oil) in DMF was stirred for 2 hours. The mixture was diluted with diethyl ether and washed with water. The organic solution was dried (MgSO4), filtered and evaporated. Ethyl 6-[N-(2-benzyloxy-5-bromobenzyl)-N-(tert-butoxycarbonyl)amino]-3-pyridazinecarboxylate was isolated by flash chromatography, eluting with 2% ethyl acetate in CH2Cl2. Yield: 1.7 g.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:31])[C:9]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:10]([CH:12]([N:14]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:13])[N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:14][CH:12]([C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]2[C:8](=[O:31])[C:9]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:13]
Reactant: Cc1cccc2nc(C(C)N3C(=O)c4ccccc4C3=O)c(-c3ccccc3)c(=O)n12
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc2nc(C(C)N)c(-c3ccccc3)c(=O)n12

Procedure:
A solution of 2-(1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)-ethyl)isoindoline-1,3-dione (0.30g, 0.73 mmol) and hydrazine monohydrate (0.36 mL, 7.3 mmol) in EtOH (14.7 mL) was stirred at 90° C. for 1 h. The mixture was loaded onto silica gel and purified by MPLC (eluted with a gradient of 0-100% (1:10:90 NH4OH:MeOH:DCM solution) in DCM) to afford 2-(1-aminoethyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one as a light yellow foam. Mass Spectrum (ESI) m/e=280.3 (M+1).
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C[O-].[Na+].C(O[CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19])C>C(O)C>[NH2:21][C:20]1[N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[N:9]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: NNC1CCCCC1
Reactant: CCOCC(C#N)C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnn(C2CCCCC2)c1N
Temperature: 70 °C
Yield: 66.2 %

Procedure:
To cyclohexylhydrazine hydrochloride (7.52 g, 50 mmol) generated above in 500 mL absolute ethanol was added sodium methoxide (Aldrich, 2.7 g, 50 mmol). The mixture was stirred briefly and ethoxymethylmalononitrile (Acros, 6.11 g, 50 mmol) was added in small portions over twenty minutes. The reaction mixture was then heated at 70° C. under argon overnight. On cooling, the reaction was concentrated and subjected to flash chromatography on silica gel (1:1 hexane:ethyl acetate) affording 6.3 g (66%) of a light brown solid. Compound 8: mp 99-103° C.; MS (ES+ calculated: 190.25; found: 191.15 M+H). HPLC (97% purity, retention time 11.135 minutes—Method A); 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 1H), 6.49 (br s, 2H), 4.02 (m, 1H), 1.80-1.10 (m, 10H).
Reaction SMILES: [CH3:1][N:2]([CH3:55])[C:3](=[O:54])[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14][C@:15]23[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:16]2[C@@H:17]2[C@@:30]([CH3:33])([CH2:31][CH2:32]3)[C@@:29]3([CH3:34])[C@@H:20]([C@:21]4([CH3:47])[C@@H:26]([CH2:27][CH2:28]3)[C:25]([CH3:36])([CH3:35])[C:24]([C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43]C)=[O:42])=[CH:39][CH:38]=3)=[CH:23][CH2:22]4)[CH2:19][CH2:18]2)[CH2:8][CH2:7]1)=[O:5].[OH-].[Na+]>O1CCOCC1>[CH3:55][N:2]([CH3:1])[C:3](=[O:54])[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14][C@:15]23[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:16]2[C@@H:17]2[C@@:30]([CH3:33])([CH2:31][CH2:32]3)[C@@:29]3([CH3:34])[C@@H:20]([C@:21]4([CH3:47])[C@@H:26]([CH2:27][CH2:28]3)[C:25]([CH3:36])([CH3:35])[C:24]([C:37]3[CH:38]=[CH:39][C:40]([C:41]([OH:43])=[O:42])=[CH:45][CH:46]=3)=[CH:23][CH2:22]4)[CH2:19][CH2:18]2)[CH2:8][CH2:7]1)=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C(=O)N(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C(=O)N(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 82 °C
Yield: 43.3 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(2-(dimethylamino)-2-oxoacetyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (40 mg, 0.053 mmol) and sodium hydroxide (0.530 mL, 0.530 mmol) in dioxane (1 mL) was heated up at 82° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered and the clear solution was purified by HPLC to provide the title compound as a white solid (17 mg, 41%). LCMS: m/e 741.65 (M+H)+, 2.29 min (method 11). 1H NMR (400 MHz, Acetic) δ 7.99 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 5.33 (d, J=4.5 Hz, 1H), 4.82 (s, 1H), 4.71 (s, 1H), 4.14-3.78 (m, 2H), 3.75-3.36 (m, 6H), 3.22 (br. s., 4H), 3.03 (s, 3H), 3.00 (s, 3H), 2.92-2.75 (m, 1H), 2.29-1.05 (m, 22H), 1.73 (s, 3H), 1.20 (s, 3H), 1.10 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[N:13]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([CH:26]2CCCC[C:27]2=[O:32])C=CC=CC=1.O1C2(CCNCC2)OCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]1([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[N:13]2[CH2:18][CH2:17][C:16]3([O:32][CH2:27][CH2:26][O:19]3)[CH2:15][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCN([C@@H]2CCCC[C@@H]2c2ccccc2)CC1
Reactant: O=C1CCCCC1c1ccccc1
Agent: C1CC2(CCN1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc([C@H]2CCCC[C@H]2N2CCC3(CC2)OCCO3)cc1
Yield: 68 %

Procedure:
Preparation of (+/−)-cis-1-(2-Phenyl-cyclohexyl)-piperidin-4-one. To a solution of 2-phenyl-cyclohexanone (46.0 g, 264 mmol) and 1,4-dioxa-8-aza-spiro[4,5]decane (31.5 g, 220 mmol) in toluene (380 ml), p-toluenesulphonic acid monohydrate (4.18 g, 22.0 mmol) was added and the mixture was heated to reflux in an apparatus equipped with a Dean-Stark trap for 24 h. The reaction mixture was then evaporated and the resulting crude enamine dissolved in 1,2-dichloroethane (900 ml) and acetic acid (8.00 ml). To this solution, sodium triacetoxyborohydride (69.0 g, 308 mmol) was added in portion. After a total reaction time of 2.5 h, the reaction mixture was treated with 2N NaOH (250 ml) and extracted with dichloromethane. The pooled organic extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated. Purification of the crude product over a silica gel plug (10:1) with n-heptane/ethyl acetate 10:1 then n-heptane/ethyl acetate 9:1 and finally ethyl acetate as eluent provided (+/−)-8-(cis-2-phenyl-cyclohexyl)-1,4-dioxa-8-aza-spiro[4,5]decane (44.8 g, 68%) as a yellow oil, MS (ISP): m/e=302.4 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:20])([CH3:19])[C:14](=[O:18])[NH:15]2)=[CH:11][C:10]=1[NH2:21])=O.Cl>C(O)C>[CH3:19][C:13]1([CH3:20])[C:12]2[C:16](=[CH:17][C:9]3[NH:8][C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[N:21][C:10]=3[CH:11]=2)[NH:15][C:14]1=[O:18]
Reactant: CC1(C)C(=O)Nc2cc(NC(=O)c3ccco3)c(N)cc21
Agent: Cl
Solvent: CCO
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4ccco4)nc3cc21

Procedure:
5.7 g. (20 mmol) 6-furanoylamino-5-amino-3,3-dimethylindolin-2-one are heated for 1 hour at 80° C. in 200 ml. ethanol and 40 ml. concentrated hydrochloric acid. The solution is evaporated to dryness, rendered alkaline with 2N aqueous ammonia solution and extracted with methylene chloride. The organic phase is evaporated and the residue purified over silica gel (elution agent: methylene chloride/ammonia-saturated methanol 20:1 v/v). There is obtained 1.8 g. (33.3% of theory) of the desired product; m.p. 311°-316° C. after recrystallisation from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH:16]1[CH2:19][CH:18]([N:20]([CH2:25][C@@H:26]2[C@@H:33]3[C@@H:29]([O:30][C:31]([CH3:35])([CH3:34])[O:32]3)[C@H:28]([N:36]3[C:40]4[N:41]=[CH:42][N:43]=[C:44]([NH:45][CH2:46][C:47]5[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=5[O:55][CH3:56])[C:39]=4[CH:38]=[CH:37]3)[CH2:27]2)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:17]1>C(O)(=O)C>[C:8]([C:6]1[CH:5]=[CH:4][C:3]2[NH:12][C:13]([CH2:14][CH2:15][CH:16]3[CH2:19][CH:18]([N:20]([CH2:25][C@@H:26]4[C@H:33]5[O:32][C:31]([CH3:34])([CH3:35])[O:30][C@H:29]5[C@H:28]([N:36]5[C:40]6[N:41]=[CH:42][N:43]=[C:44]([NH:45][CH2:46][C:47]7[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=7[O:55][CH3:56])[C:39]=6[CH:38]=[CH:37]5)[CH2:27]4)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:17]3)=[N:1][C:2]=2[CH:7]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC(C)C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC(C)C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Yield: 53.8 %

Procedure:
A solution of N-(2-amino-4-(tert-butyl)phenyl)-3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isobutyl)amino)cyclobutyl)propanamide (1.71 g, 2.19 mmol) in Acetic acid (6 ml) was stirred overnight at 60° C., the volatiles were removed in vacuo and the remaining residue was purified by flash chromatography (SiO2, DCM I 7N NH3 in MeOH 94:6) to yield the desired compound (0.9 g) as a foam.
Reaction SMILES: C(O[C:4]1[C:5](=[O:14])[C:6](=[O:13])[C:7]=1[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])C.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][NH2:21].[K+].[Br-]>>[C:9]([NH:8][C:7]1[C:6](=[O:13])[C:5](=[O:14])[C:4]=1[NH:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=1)([CH3:10])([CH3:11])[CH3:12]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CCOc1c(NC(C)(C)C)c(=O)c1=O
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)Nc1c(NCc2cccc(C(F)(F)F)c2)c(=O)c1=O
Yield: 73 %

Procedure:
The title compound was prepared according to the procedure for example 1-step 2 except that 3-ethoxy-4-(tert-butylamino)-cyclobut-3-ene-1,2-dione was used in place of (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione and 3-trifluoromethyl-benzylamine was used in place of 4-fluoro-benzylamine. Yield: 73%; mp: 237-239° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.36 (s, 9H), 4.81-4.87 (m, 2H), 7.57 (s, 1H), 7.60-7.77 (m, 4H), 7.82 (brm, 1H); IR (KBr, cm-1): 3233m, 3059w, 2973w, 1793w, 1653s, 1571s, 1540s, 1471m, 1447m, 1354m, 1166m, 1127m; MS (CI) m/z (relative intensity): 327 (M+ +H, 80); Anal. Calcd. for C16H17 F3N2O2 : C, 58.89; H, 5.25; N, 8.58. Found: C, 58.99; H, 5.23; N, 8.47.
Reaction SMILES: Cl.N[C:3]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].[C-:25]#[N:26].[K+]>O.C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2].CCOC(C)=O>[Cl:14][C:13]1[C:3]([C:25]#[N:26])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cccc(Cl)c1N
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cccc(Cl)c1C#N
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Hydrochloric acid (4.57 mL, 150 mmol) was added to a suspension of the ethyl 2-amino-3-chlorobenzoate (1.5 g, 7.51 mmol) in water (40 mL) and the mixture was cooled to 0° C. [note: compound did not go into solution] To this cooled mixture was added sodium nitrite (0.518 g, 7.51 mmol) portionwise keeping the temperature below 5° C. After addition the reaction was stirred for 40 mins. A small amount of toluene (3 ml) was added to aid dissolution. The mixture was then basified to pH˜6 by the addition of Na2CO3. In a separate flask potassium cyanide (2.202 g, 33.8 mmol) was added portionwise to a biphasic solution of copper(II) sulfate (1.439 g, 9.02 mmol) in water (15 mL) and toluene (15 mL) at 0° C. [note: exothermic reaction] After addition the now brown mixture was heated to 60° C. To this was added the diazonium salt dropwise via a dropping funnel (mixture kept at 0° C. during addition). After addition the reaction was stirred at 70° C. for 1 hr. The reaction was cooled and EtOAc was added. The organic layer was collected, dried (Na2SO4) and the solvent evaporated to afford a crude dark brown oil. LCMS: 2 major peaks+1 minor peak present. (One major peak corresponds to the SM—no mass ion observed). The crude material was purified by chromatography, SP4, 100 g SNAP, 0 to 100% EtOAc/i-Hexane (fasted eluting first). The desired product was identified in 398 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:57]([C:59]1[CH:64]=[C:63]([I:65])[CH:62]=[CH:61][N:60]=1)[NH2:58]>CN(C=O)C.O>[CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:58][NH:57][C:59]3[CH:64]=[C:63]([I:65])[CH:62]=[CH:61][N:60]=3)=[O:13])=[CH:15][CH:16]=2)[C@H:3]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OC(=O)N(c2ccc(C(=O)O)cc2)[C@H]1c1ccccc1
Reactant: NNc1cc(I)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(C(=O)NNc3cc(I)ccn3)cc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
(S)-4-(5,5-Dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoic acid (1500 mg, 4.82 mmol) was dissolved in DMF (9.636 mL) at room temperature. To the reaction mixture were added N-ethyl-N-isopropylpropan-2-amine (2.514 mL, 14.45 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.832 g, 4.82 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) and 2-hydrazinyl-4-iodopyridine (1.132 g, 4.82 mmol). The vial was sealed and immersed in a 55° C. oil bath. After stirring overnight, LC-MS indicated complete conversion. After cooling to room temperature, the reaction mixture was transferred to water in a flask in an ice/water bath. The solution was washed with DCM (3×50 mL). The combined organic layers were then washed with water (2×50 mL) and brine (50 mL). The organic extract was dried over Na2SO4. The residual material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% MeOH in DCM, to provide (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-N′-(4-iodopyridin-2-yl)benzohydrazide (1.53 g, 2.90 mmol, 60.1% yield) as an off-white solid. m/z (ESI) 529.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](B(O)O)=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:16].[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](=[O:16])[CH:7]=[C:8]([CH3:11])[NH:9][CH:10]=1
Reactant: COCOc1cnc(C)cc1B(O)O
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1c[nH]c(C)cc1=O
Yield: 100 %

Procedure:
To a solution of 5-(methoxymethoxy)-2-methylpyridin-4-ylboronic acid (500 mg, 2.54 mmol) in tetrahydrofuran (12.7 mL), an aqueous solution of hydroxide peroxide (purity 30%) (2.9 mL, 25.4 mmol) was added at room temperature, and the resultant mixture was stirred at room temperature for 4 hours. The reaction solution was added with a saturated aqueous solution of sodium persulfate and concentrated in vacuo. The obtained residue was washed and filtered with chloroform/methanol, and 5-(methoxymethoxy)-2-methylpyridin-4(1H)-one (440 mg, yield >100%) was obtained as a yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH:22]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][N:27]=2)[CH2:25][CH2:24][CH2:23]1.[S].C(O)(=O)C>C(O)C>[CH:22]1([C:26]2[N:31]=[C:30]([C:32]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]6[CH2:21][CH2:20][CH2:19][CH2:18]6)=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH:29]=[CH:28][N:27]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: O=Cc1ccnc(C2CCC2)n1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: [S]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CCC5)n4)[nH]c3n2)C1)N1CCCC1
Reaction time: 16 h

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (135.9 mg, 0.5 mmol) in ethanol was added 2-cyclobutylpyrimidine-4-carbaldehyde (76.2 mg, 0.5 mmol), sulfur (30.1 mg, 0.9 mmol) and acetic acid (0.15 mL) at room temperature under nitrogen. The reaction mixture was stirred for 16 h at reflux. The solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via preparative TLC to afford the title compound as a yellow solid. MS (ES+APCI) (M+H) 432.1; LCMS retention time 2.567 min (Method G).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([NH2:25])=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)(=[O:3])[CH3:2].[F:26][C:27]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:37][C:38](O)=[O:39].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([NH:25][C:38](=[O:39])[CH2:37][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33]([F:34])([F:35])[F:36])[C:27]=2[F:26])=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1N
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1NC(=O)Cc1cccc(C(F)(F)F)c1F
Temperature: 40 °C

Procedure:
A reaction vial was charged with acetic acid 2-[6-(2-acetoxy-ethylamino)-5-amino-1-oxo-1H-isoquinolin-2-yl]-ethyl ester (100.00 mg, 0.000 28788 mol), 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid (76.74 mg, 0.0003454 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (274 mg, 0.000720 mol), N,N-diisopropylethylamine (0.125 mL, 0.000720 mol) and methylene chloride (3 mL, 0.05 mol). The reaction was heated at 40° C. for 5 h. The solvent was removed under reduced pressure and the residue purified by flash chromatography to afford the product as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[N:32]=[C:31]6[S:33][C:34]([NH:36]C(=O)C7C=CC=CC=7)=[N:35][C:30]6=[CH:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[N:32]=[C:31]6[S:33][C:34]([NH2:36])=[N:35][C:30]6=[CH:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1ncnc(N2CCOc3ccc(-c4ccc5nc(NC(=O)c6ccccc6)sc5n4)cc3C2)c1Cc1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ncnc(N2CCOc3ccc(-c4ccc5nc(N)sc5n4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 37.2 %

Procedure:
A solution of N-[5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)[1,3]thiazolo[5,4-b]pyridin-2-yl]benzamide (84 mg, 0.14 mmol) in 70% aqueous sulfuric acid (2 mL) was heated to reflux for thirty minutes. On cooling to room temperature the pH of the mixture was adjusted to ˜5 by the addition of 50% aqueous sodium hydroxide. Concentration and purification by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) provided 5-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)[1,3]thiazolo[5,4-b]pyridin-2-amine (26 mg, 37%). 1H NMR (400 MHz, d6-DMSO): 8.44 (d, 1H), 8.36 (s, 1H), 8.08 (d, 1H), 8.01 (br s, 2H), 7.52 (dd, 1H), 7.16-7.10 (m, 4H), 7.00 (d, 1H), 6.90 (d, 1H), 4.48 (s, 2H), 4.28 (m, 2H), 3.96 (s, 2H), 3.76 (m, 2H), 2.14 (s, 3H). MS (EI) for C27H23FN6OS: 499 (MH+).