Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)=[O:19])[CH2:14][CH2:13]2)[CH2:7]1)=O)C.O.[OH-].[Li+].Cl.[N:42]1([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(N(CC)C(C)C)(C)C>O1CCCC1.O.ClCCl.C1(C)C(C)=CC=CC=1.ClCCl.CO>[C:51]([O:50][C:48]([N:42]1[CH2:47][CH2:46][N:45]([C:4]([CH:6]2[CH2:11][CH2:10][CH2:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([C:20]4[CH:25]=[C:24]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:23]=[C:22]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:21]=4)=[O:19])[CH2:14][CH2:13]3)[CH2:7]2)=[O:3])[CH2:44][CH2:43]1)=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCOC(=O)[C@@H]1CCCN(C2CCN(C(=O)c3cc(-c4ccccc4)nc(-c4ccccc4)c3)CC2)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCCN(C3CCN(C(=O)c4cc(-c5ccccc5)nc(-c5ccccc5)c4)CC3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
(3R)-1′-[2,6-Diphenyl-pyridine-4-carbonyl]-[1,4′]bipiperidinyl-3-carboxylic acid ethyl ester (1.96 g, 3.94 mmol) was dissolved in tetrahydrofuran (20 mL) and lithium hydroxide monohydrate (3 eq, 0.5 g) in water (10 mL) was added. The two phase mixture was stirred for 16 hr at ambient temperature. Thin layer chromatography (19:1 dichloromethane-methanol) indicated no remaining starting material. 2M hydrochloric acid (6 mL) was added to adjust the pH to ˜5, about 2× the volume of the xylene was added and the mixture was evaporated to give a pale oil. This was further dried briefly under high vacuum then suspended in ethanol-free chloroform (˜30 mL), thionyl chloride added (5 mL) and the mixture heated under reflux, directing the evolved gases to a scrubber. After 30 minutes a further aliquot of thionyl chloride (5 mL) and chloroform (20 mL) were added and the reflux continued. After all the solid had dissolved (˜2 hr) the solvent was evaporated under vacuum. Anhydrous dichloromethane (30 mL) was added followed by a mixture of tert-butyl 1-piperazinecarboxylate (1.1 eq, 810 mg) and N,N-diisopropylethylamine (5 eq, 3.4 mL) in anhydrous dichloromethane (10 mL) was added. The cloudy mixture was stirred for 16 hr at ambient temperature then washed with 0.1M sodium hydroxide solution and the aqueous layer was extracted with dichloromethane (×3). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue was purified by chromatography on 100 g silica gel/5% methanol-dichloromethane to give the title compound (1.78 g, 71%).
Reaction SMILES: O1CCCC1.[C:6]1([S:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[C:6]1([S:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:22][N:21]=3)=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Sc2ccccc2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncccc1-c1cc(Cc2ccc(Sc3ccccc3)nc2)no1
Temperature: 50 °C
Reaction time: 4 h
Yield: 23.5 %

Procedure:
To a tetrahydrofuran (5 mL) solution of (6-phenylsulfanyl-pyridin-3-yl)-acetohydroximoyl chloride (149 mg, 0.54 mmol) described in Manufacturing Example 97-1-4 and 3-ethynyl-pyridin-2-ylamine (15 mg, 0.13 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (80 μL, 0.57 mmol), which was stirred for 4 hours at 50° C. under nitrogen atmosphere. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) and then further purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (11 mg, 23%).
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]2[O:8]C(C)(C)[O:10][CH:6]2[CH:5]([O:13][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:4][C:3]1=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)C>C(O)C>[CH2:1]=[C:2]1[CH:7]([OH:8])[CH:6]([OH:10])[CH:5]([O:13][Si:14]([C:27]([CH3:30])([CH3:28])[CH3:29])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:4][C:3]1=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: C=C1C(=CC(=O)OCC)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2OC(C)(C)OC12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: C=C1C(=CC(=O)OCC)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(O)C1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.9 %

Procedure:
Ethyl (2-methylene-3,4-(dimethylmethylenedioxy)-5-(tert-butyldiphenylsilyloxy)cyclohexylidene)acetate (0.506 g) was dissolved in 10 ml of ethanol, and a catalytic amount of p-toluenesulfonic acid was added, followed by stirring the mixture at room temperature for 5 hours. Water was added to the reaction mixture, and extraction was conducted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.405 g of ethyl (2-methylene-3,4-dihydroxy-5-(tert-butyldiphenylsilyloxy)cyclohexylidene)acetate having the following property.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[C:32]([C:39]1[CH:40]=[N:41][N:42]([CH2:45][CH3:46])[C:43]=1[CH3:44])[N:33]2[CH3:38]>C(O)C>[CH2:45]([N:42]1[C:43]([CH3:44])=[C:39]([C:32]2[N:33]([CH3:38])[C:34]3[C:30]([N:31]=2)=[C:29]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]2)[N:37]=[CH:36][N:35]=3)[CH:40]=[N:41]1)[CH3:46]
Reactant: CCn1ncc(-c2nc3c(Cl)ncnc3n2C)c1C
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc(-c2nc3c(N4CCC(n5c(=O)[nH]c6ncccc65)CC4)ncnc3n2C)c1C
Temperature: 75 °C
Yield: 73.1 %

Procedure:
To a solution of 1-piperidin-4-yl-1,3-dihydro-2H-imidazolo[4,5-b]pyridin-2-one dihydrochloride (0.22 g, 0.78 mmol) in an anhydrous ethanol (8 mL) and diisopropylethylamine (0.56 mL) was added 6-chloro-8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purine (0.18 g, 0.65 mmol). The reaction mixture was heated to 75° C. for 18 hours. The resulting solution was cooled to room temperature, and concentrated under reduced pressure. The solids were dissolved in dichloromethane (15 mL), and the solution was washed with water (10 mL). The organic layer was concentrated under reduced pressure. The resulting solids were collected by vacuum filtration, and triturated with 5 mL of ethanol at 75° C. for 30 min. The precipitate was collected by vacuum filtration to give 218 mg (73% yield) of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 11.54 (s, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.85 (d, 1H), 7.47 (d, 1H), 6.92 (dd, 1H), 5.60 (broad s, 2H), 4.55 (m, 1H), 4.14 (q, 2H), 3.77 (s, 3H), 3.22 (m, 2H), 2.51 (s, 3H), 2.26 (m, 2H), 1.86 (d, 2H), 1.33 (t, 3H); MS (EI) for C23H26N10O: 459.3 (MH+).
Reaction SMILES: [Br-].[Br-].[NH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([NH2:12])[N:5]=1.[Br:13][CH2:14][C:15](=O)[CH:16]=NO>CO>[NH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]2[C:6](=[N:12][CH:16]=[C:15]([CH2:14][Br:13])[N:11]=2)[N:5]=1
Reactant: Nc1nc(N)c(N)c(N)n1
Reactant: O=C(C=NO)CBr
Agent: [Br-]
Solvent: CO
Product: Nc1nc(N)c2nc(CBr)cnc2n1
Yield: 88 %

Procedure:
A suspension of 5 mmol 2,4,5,6-tetraminopyrimidine dibromide in 50 ml methanol was treated with a solution of 7.5 mmol β-bromopyruvaldoxime in 10 ml of methanol at reflux temperature for 2 h. The 2,4-diamino-6-(bromomethyl)pteridine was collected after neutralization with concentrated NH3 at room temperature, washed with methanol, ether and dried at 100° C. in an oven. 1H NMR (250 MHz, ppm, DMSO-d6), δ 8.84 (s, 1H, C7—H). The yield was 88%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc(N)c2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: Cc1ccc2cccc(NS(=O)(=O)c3ccccc3)c2n1
Yield: 41.9 %

Procedure:
In the similar fashion using route 14 general procedure 27, 2-methyl-8-aminoquinoline (Intermediate 22) (200 mg, 1.2 mmol), benzenesulfonyl chloride (230 mg, 1.2 mmol) and DMAP (cat.) gave the title compound (150 mg, 43%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][NH:27][CH2:26][CH2:25][NH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1.C(N(CC)CC)C>CN(C)C=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][N:27]([C:2]3[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][N:13]=[CH:12][N:11]=4)[N:3]=3)[CH2:26][CH2:25][NH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: COc1cc(F)ccc1C1CNCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(F)ccc1C1CN(c2nc(-c3ccncn3)cc(=O)n2C)CCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
2-Chloro-3-methyl-6-(4-pyrimidyl)-pyrimidin-4-one (223 mg, 1:0 mmol) was added to an ice-cooled solution of 2-(4-fluoro-2-methoxyphenyl)piperazine (210 mg, 1.0 mmol), triethylamine (0.15 ml, 1.1 mmol) in N,N-dimethylformamide (10 ml) and stirred at that temperature for 0.5 hr and then at room temperature for 3 hours. Reaction was quenched by ice-water and the filtrate was washed with water and dried to give 2-(2-(4-fluoro-2-methoxyphenyl)piperazin-4-yl)-3-methyl-6-(4-pyrimidyl)-pyrimidin-4-one (262 mg, 66%).
Reaction SMILES: [Mg].[CH2:2]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:2]([C:7]1[CH:12]=[CH:11][C:10]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 24 h
Yield: 62 %

Procedure:
Magnesium (1.06 g: 88.3 mmol) and 4-n-pentylbromobenzene (10.0 g: 44.01 mmol) were dissolved in 50 ml of dried tetrahydrofuran, and a Grignard reagent was prepared from the mixture. To the Grignard reagent was added 11.6 g (44.1 mmol) of 4-(benzyloxy)bromobenzene synthesized in the step (i). The reaction system was purged with argon. To the reaction system was added 600 mg of dichloro(1,4-diphenylphosphinobutane)palladium (II) [Pd(dppb)Cl2], and the reaction was conducted for 24 hours. The reaction mixture was poured into an iced water, and the resultant mixture was acidified by adding hydrochloric acid. The resultant solid was collected by filtration, washed with water, dried, and recrystallized from a mixed solvent of hexane/toluene to give 9.0 g (27.3 mmol) of 4-n-pentyl-4′-benzyloxybiphenyl.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:10])[C:8]=1[F:9].[B:12](OC)([O:15]C)[O:13]C.Cl>>[F:2][C:3]1[CH:4]=[C:5]([B:12]([OH:15])[OH:13])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Product: OB(O)c1cc(F)c(F)c(F)c1
Temperature: 32 °C
Reaction time: 2.5 h

Procedure:
A nitrogen- or argon-inertized reactor was initially charged with 83.2 g (3.42 mol) of magnesium turnings and then 1646.2 g of dry, unstabilized tetrahydrofuran were added. 30 g (0.14 mol) of 3,4,5-trifluorobromobenzene were added dropwise at 25° C. with stirring and the startup of the Grignard reaction was awaited. The startup of the Grignard reaction was perceptible by a spontaneous temperature increase to approx. 32° C. Subsequently, 571.9 g (2.71 mol) of further 3,4,5-trifluorobromobenzene were metered in at 25-35° C. within 5 h. To complete the reaction, the mixture was stirred at 25-30° C. for a further 2 h. A 2nd reactor was initially charged with a solution of 328.0 g (3.16 mol) of trimethyl borate and 452 g of dry, unstabilized tetrahydrofuran, which were precooled to −5° C. Thereafter, the Grignard solution was metered in from the 1st reactor within 2.5 h. The excess magnesium remained in the 1st reactor. After the metered addition had ended, the mixture was stirred at 20-25° C. for another 2 h. For hydrolysis, 1326.1 g (2.76 mol) of 7.6% hydrochloric acid were then metered in at 25° C., after which the mixture was stirred at 25° C. for another 1 h. The mixture was heated to 50° C. and the phases were separated. Thereafter, the organic phase was re-extracted with 603.9 g of water at 50° C. and the washing water phase was removed again. Subsequently, the organic phase was concentrated by distilling off a tetrahydrofuran/water mixture. This afforded 1032.6 (82%) of a 40% solution of 3,4,5-trifluorophenylboronic acid in tetrahydrofuran, which was used directly for the subsequent reactions.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:14]2[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:27]([NH2:29])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:14]2[CH2:15][CH2:16][C@@H:17]([CH3:20])[CH2:18][CH2:19]2)[CH2:10][C@H:9]1[C:27]#[N:29])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N(C(=O)C(C)(C)C)[C@H]2CC[C@@H](C)CC2)C[C@H]1C(N)=O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1C[C@@H](N(C(=O)C(C)(C)C)[C@H]2CC[C@@H](C)CC2)C[C@H]1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of BOC-(2S,4S)-2(aminocarbonyl)-4-[(2,2-dimethylpropanoyl)(cis-4-methylcyclohexyl)amino]pyrrolidine (576 mg, 1.41 mmol) prepared in Step D of Example A7 in DCM (5 ml) was added dropwise TFAA (0.2 ml, 1.41 mmol), and the solution was stirred at rt for 2 h. After the reaction finished, the solution was concentrated in vacuo. The residue was diluted with EtOAc, and washed with brine. The organic solution was dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc:Hex=1/2) to give the title compound (514 mg, 93%).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18].CO.S(=O)(=O)(O)O>O>[F:23][C:15]([F:24])([C:16]([F:21])([F:22])[C:17]([F:19])([F:20])[F:18])[CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][OH:7]
Reactant: FC(F)(F)C(F)(F)C(F)(F)COCCOCCOC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: OCCOCCOCC(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
Then, 17.4 g (0.047M) of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecyl tetrahydropyranyl ether (purity: 99% or above), 35 ml of methanol, 18 ml of water and 2.2 ml of concentrated sulfuric acid were placed in a 100 ml-reaction vessel, followed by stirring for 2 hours at room temperature. The reaction mixture was poured into water and saturated with common salt. The saturated reaction mixture was subjected to extraction with ethyl acetate, washed with saturated common salt water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent to obtain a residue. The residue was subjected to reduced-pressure distillation to obtain 6.4 g of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecanol (b.p.: 86°-87° C./6 mmHg).
Reaction SMILES: B.CSC.[CH2:5]([O:7][C:8](=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][CH:17]=O)[CH:11]=1)[CH3:6].Cl>C1COCC1>[CH2:5]([O:7][C:8](=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][CH3:17])[CH:11]=1)[CH3:6]
Reactant: CCOC(=O)Cc1cccc(NC=O)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CCOC(=O)Cc1cccc(NC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
A solution of borane-dimethylsulphide complex (2M in THF; 20 mL) was added to an ice cold solution of 3-(formylamino)phenylacetic acid ethyl ester (4.1 g; 0.02 mol; from step (i) above) in THF (dry; 100 mL) and the reaction mixture was stirred for 1 hour. The resultant solution was poured onto diluted HCl and the mixture left for 15 minutes, whereafter it was washed with ether to remove unreacted material. The aqueous solution was made alkaline (NaHCO3) and extracted with ether (3 times). The combined organic phases were washed with water, dried (Na2SO4) and evaporated to yield 3.0 g (78%) of the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=1.C1C(=O)N([Cl:41])C(=O)C1>>[Cl:41][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@H:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH3:24])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)N(C)C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Cl
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)N(C)C(=O)OC(C)(C)C)cc1
Yield: 20 %

Procedure:
Following General Procedure H, (R)-tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethyl(methyl)carbamate (200 mg, 0.43 mmol) was reacted with NCS (69 mg, 0.52 mmol) to afford the desired product (43 mg, 20%) as a yellowish solid. ESI MS m/z 499 [C26H27ClN2O4S+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH:8]=3.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[CH3:27].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CO>[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[C:9]([C:15]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[O:16])[CH:8]=4)=[CH:31][CH:30]=1)[CH3:27]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3c2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 17.6 %

Procedure:
3-Bromo-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (57 mg, 0.142 mmol), 4-ethoxyphenylboronic acid (35.3 mg, 0.213 mmol), Pd(Ph3P)4 (16.37 mg, 0.014 mmol) and aqueous Na2CO3 (2M) (0.177 mL, 0.354 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was degassed and filled with N2. then stirred at 100° C. for 12 hrs. The reaction mixture was concentrated and purified using preparative HPLC to give 11.1 mg of titled product. MS (ESI) m/z 444.21 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.53 (s, 1H), 8.64 (s, 1H), 8.37 (bs, 1H), 8.29 (m, 2H), 7.81 (m, 3H), 7.56 (bs, 1H), 7.22 (d, 1H, J=8), 7.07(m, 2H), 4.10 (q, 2H, J=6.9), 3.64 (bm, 8H), 1.37 (t, 3H, J=6.9).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:21]2[N:25]3[CH2:26][CH2:27][CH2:28][C:29](CC(O)C)([O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=4)[C:24]3=[N:23][N:22]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[O:19][C:18]([CH3:20])=[N:17][CH:16]=1)C1C=CC=CC=1>CO.[C].[Pd]>[F:38][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][C:34]=1[F:37])[O:30][C:29]1([C:9]([OH:8])([CH3:10])[CH3:14])[CH2:28][CH2:27][CH2:26][N:25]2[C:21]([C:11]3[CH:12]=[CH:13][C:14]([C:15]4[O:19][C:18]([CH3:20])=[N:17][CH:16]=4)=[C:9]([OH:8])[CH:10]=3)=[N:22][N:23]=[C:24]12
Reactant: Cc1ncc(-c2ccc(-c3nnc4n3CCCC4(CC(C)O)Oc3ccc(F)c(F)c3)cc2OCc2ccccc2)o1
Agent: [Pd]
Solvent: CO
Product: Cc1ncc(-c2ccc(-c3nnc4n3CCCC4(Oc3ccc(F)c(F)c3)C(C)(C)O)cc2O)o1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 137.9 %

Procedure:
A mixture of 2-{(3-[3-(benzyloxy)-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-(3,4-difluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol (100 mg) and 5% palladium-carbon (100 mg) in methanol (1.5 mL) was stirred at room temperature for 45 min under a hydrogen atmosphere. The mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (58.1 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([CH3:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21].Cl>O1CCOCC1.C(O)(C)C>[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH:33][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[C:11]([NH:13][CH3:14])=[O:12])[C:5]([CH3:19])=[CH:4][N:3]=3)[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(C)c(Nc4ccccc4C(=O)NC)n3)cc2CC1
Yield: 38.7 %

Procedure:
2-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-N-methyl-benzamide (32 mg, 0.12 mmol) and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (24 mg, 0.13 mmol) were combined with 1 drop of a solution of 4N hydrochloric acid in dioxane and 2 mL isopropanol and subjected to microwave irradiation (CEP) at 170° C. for 150 minutes. The reaction mixture was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The dichloromethane extract was separated, dried (sodium sulfate), and concentrated to afford a material which was purified on silica gel (methanol:dichloromethane gradient elution) to afford 20 mg (39%) of a white foam -2-[2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-5-methyl-pyrimidin-4-ylamino]-N-methyl-benzamide. MS: 431.20 (M+H); 1H NMR (d6-dmso): δ 11.20 (s, 1H), δ 8.99 (s, 1H), δ 8.86 (d, J=8 Hz, 1H), δ 8.74 (d, J=4 Hz, 1H), δ 7.97 (s, 1H), δ 7.75 (d, J=8 Hz, 1H), δ 7.49 (s, 1H), δ 7.45 (t, J=8 Hz, 1H), δ 7.38 (d, J=8 Hz, 1H), δ 7.08 (t, J=8 Hz, 1H), δ 6.97 (d, J=8 Hz, 1H), δ 2.82 (d, J=6 Hz, 3H), δ 2.80 (m, 2H), δ 2.70-2.40 (m, 8H), δ 2.10 (s, 3H), δ 1.01 (t, J=8 Hz, 3H).