Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29]
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccccc3Cl)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccccc1Cl

Procedure:
The 2-trifluoroacetamido-3-(2-chlorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (10.8 g, 24.2 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 7.45 g. (88.5%). EA, MS(FD).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH:14]1([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[O:30][CH3:31])[C:23]([C:32]([NH2:34])=O)=[CH:22]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C.O1CCOCC1>O>[CH:14]1([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[O:30][CH3:31])[C:23]([C:32]#[N:34])=[CH:22]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COc1cccc2c(C(N)=O)cn(CC3CCCCC3)c12
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cccc2c(C#N)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
Trifluoroacetic anhydride (12.0 g, 57.1 mmol) was added dropwise to a mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid amide (4.1 g, 14.3 mmol), triethylamine (11.6 g, 115 mmol), and 1,4-dioxane (250 ml) under ice-water cooling. The resulting mixture was stirred at room temperature for 12 h. Water (30 ml) was added and the resulting mixture was concentrated in vacuo. Water (300 ml) was added to the obtained residue, and the mixture was extracted with dichloromethane (4×300 ml). The organic layers were combined, washed with 5% aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was purified by column chromatography eluting with 10% (v/v) ethyl acetate in n-heptane to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbonitrile as a crystalline solid (2.48 g).
Reaction SMILES: Br[CH:2]([C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH2:20][C:21]([NH2:23])=[S:22].C(O)C>O>[NH2:23][C:21]1[S:22][C:2]([CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:20]=1
Reactant: CCOC(=O)CCCC(Br)C(=O)c1ccc(Cl)cc1
Reactant: NC(N)=S
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCc1sc(N)nc1-c1ccc(Cl)cc1
Yield: 89.8 %

Procedure:
A mixture of ethyl 5-bromo-5-(4-chlorobenzoyl)valerate (17.4 g), thiourea (4.57 g) and ethanol (50 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give ethyl 2-amino-4-(4-chlorophenyl)-5-thiazolebutanoate (14.6 g, 85%) as pale yellow prisms. Melting point 114-115° C.
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:6](OCC)=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[OH:7][CH2:6][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: CCOC(=O)[C@@H](Cc1cccc([N+](=O)[O-])c1)NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N[C@@H](CO)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
A light suspension, under an inert atmosphere, of 1.4 g of ethyl (2R)-2-(acetylamino)-3-(3-nitrophenyl)propanoate in 13 cm3 of ethanol is cooled to a temperature of 20° C. and 0.29 g of sodium borohydride is then added thereto. The yellow solution obtained is stirred at room temperature for 18 hours. The reaction medium is then concentrated under reduced pressure (2 kPa) at a temperature in the region of 50° C., after which 10 cm3 of water are added and the mixture is extracted with twice 50 cm3 of ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1 g of N-[(1R)-2-hydroxy-1-(3-nitrobenzyl)ethyl]-acetamide is obtained in the form of pale yellow crystals melting at 135° C. 1H NMR spectrum (250 MHz, (CD3)2SO-d6, δ in ppm): 1.75 (s: 3H); 2.74 (dd, J=14 and 9 Hz: 1H); 3.02 (dd, J=14 and 5 Hz: 1H); from 3.25 to 3.45 (mt: 2H); 3.96 (mt: 1H); 4.90 (broad s: 1H); 7.59 (t, J=8 Hz: 1H); 7.70 (broad d, J=8 Hz: 1H); 7.82 (d, J=8.5 Hz: 1H); from 8.05 to 8.15 (mt: 2H).
Reaction SMILES: COC1C(SC#N)=CC(C)=C(O)C=1.COC(=O)C[O:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([S:26][C:27]#[N:28])=[CH:21][C:20]=1[CH3:29]>>[CH3:29][C:20]1[CH:21]=[C:22]([S:26][C:27]#[N:28])[C:23]([CH3:25])=[CH:24][C:19]=1[OH:18]
Reactant: COC(=O)COc1cc(C)c(SC#N)cc1C
Agent: COc1cc(O)c(C)cc1SC#N
Product: Cc1cc(SC#N)c(C)cc1O

Procedure:
The title compound was prepared in a manner analogous to compound 1B. 400 MHz 1H NMR (DMSO-d6) δ 10.0 (s, 1H), 7.35 (s, 1H), 6.73 (s, 1H), 2.3 (s, 3H), 2.04 (s, 3H); MS m/z 180 (m+1). Preparation of (2,5-Dimethyl-4-thiocyanato-phenoxy)-acetic acid methyl ester (Compound WWB)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22]Cl>CN(C)C(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][CH:11]=[N:12][C:4]=2[NH:3][CH2:1][CH3:2]
Reactant: Fc1cccc(Cl)c1CCl
Reactant: CCNc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCNc1ncnc2c1ncn2Cc1c(F)cccc1Cl
Yield: 34.1 %

Procedure:
In a procedure analogous to that of Example 9, by using 1.63 g of 6-ethylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.58 g of 2-chloro-6-fluorobenzyl chloride, there was obtained 1.04 g of 9-(2-chloro-6-fluorobenzyl)-6-ethylaminopurine as colorless needles (yield: 34%), m.p. 175°-176° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[S:14][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1.O>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][N:16]([C:13]2[S:14][CH:15]=[C:11]([CH2:10][O:9][C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:30][CH:29]=3)[N:12]=2)[CH2:21][CH2:20]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1ccc(OCc2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(COc3ccc(C(=O)O)cc3)cs2)CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
A solution of tert-butyl 4-(4-(4-methoxycarbonylphenoxymethyl)thiazol-2-yl]piperazine-1-carboxylate (820 mg, 1.89 mmol) in methanol (30 mL) and THF (10 mL) was treated with a solution of sodium hydroxide (226 mg, 5.67 mmol) in water (10 mL). The mixture was stirred at 55 ° C. for 8 hours and then concentrated by evaporation. The aqueous solution was diluted with water (10 mL) and the dilution was acidified with dilute hydrochloric acid. A resulting solid was collected by filtration to provide 4-[2-(4-tert-butoxycarbonylpiperazin-1-yl)thiazol-4-ylmethoxy]benzoic acid (800 mg, 100% yield). HNMR (dmso-d6): 7.88 (2H, d), 7.09 (2H, d), 6.91 (1H, s), 4.99 (2H, s), 3.44 (8H, m), 1.41 (9H, s).
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[Cl:25])[CH:17]=2)=[O:15])[CH2:10]1)(C)(C)C.C(Cl)Cl.CO.CCOCC>CO>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[Cl:25])[CH:17]=2)=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reaction time: 0.17 h

Procedure:
HCl(g) was bubbled through a solution of [1-(7-chloro-thieno[3,2-b]pyridine-2-carbonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (0.472 g, 1.23 mmol) in MeOH (10 mL). After 10 min, TLC (CH2Cl2/MeOH 9:1) showed the reaction to be complete. The reaction mixture was poured into Et2O (50 mL), and a white precipitate formed. The white solid was collected by filtration and washed with Et2O to afford the title compound. MS: 281.0/283.0 (MH+); HPLC Rf; 3.02 min; HPLC purity: 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[CH2:18]2.C(N(CC)CC)C.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[N:19]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[CH2:18]3)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(Cl)c(Cl)c4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 93.2 %

Procedure:
3,4-Dichlorophenylisocyanate (0.19 g, 1.0 mmol) was a added to a mixture of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.31 g, 1.0 mmol) in DMF (20 mL), followed by dropwise addition of triethylamine (0.31 mL). After 1 h, water (20 mL) was added. The solid precipitate was filtered and washed with 4% aqueous HCl, and dried in vacuo providing 1-(3,4-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.43 g, 60% yield); mp 238-240° C.; HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4. 7.87 (99.70%) 1H NMR (DMSO-d6) δ 1.98-2.01 (m, 1H), 2.33-2.46 (m, 1H), 2.57-2.62 (m, 1H), 2.86-3.00 (m, 1H), 4.34 (d, 1H, J=17.4), 4.35-4.79 (m, 3H), 5.11 (dd, 1H, J=13.2, J=5.4), 6.93 (t, 1H, J=5.7), 7.27 (dd, 1H, J=8.7, J=2.4), 7.46 (m, 3H), 7.70 (d, 1H, J=7.8), 7.86 (d, 1H, J=2.1), 9.00 (s, 1H), 10.97 (s, 1H). 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.8, 47.1, 51.5, 117.8, 118.9, 121.9, 122.3, 122.9, 123.0, 127.0, 130.3, 130.9, 140.6, 142.4, 144.5, 154.9, 167.9, 171.0, 172.9. Anal. Calcd for C21H18Cl2N4O4+0.9 CH2Cl2: C, 48.92; H, 3.71; N, 10.42. Found: C, 48.87; H, 3.48; N, 10.73.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]3=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[C:21]([NH:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[O:22])[CH:5]=[CH:4][N:3]=1.[CH3:35][O:36][C:37]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH2:52][CH2:51]3)[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:38]=1[NH2:39].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.ClCCl.CCCCCC>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[NH:23][C:21](=[O:22])[C:20]1[CH:32]=[CH:33][CH:34]=[C:18]([C:9]2[N:10]=[C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([N:44]4[CH2:45][CH2:46][CH:47]([N:50]5[CH2:51][CH2:52][N:53]([CH2:56][CH2:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH2:54][CH2:55]5)[CH2:48][CH2:49]4)=[CH:43][C:37]=3[O:36][CH3:35])[N:7]=2)[CH:19]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3c(F)cccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CO
Product: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3c(F)cccn23)n1
Temperature: 175 °C
Yield: 68.4 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)-8-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)benzamide (Example 188, step A) (90 mg, 0.19 mmol) and 2-(methyloxy)-4-(4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}-1-piperidinyl)aniline (Example 60, step B) (74 mg, 0.19 mmol) in 2,2,2-trifluoroethanol (0.90 mL) was added 4 M hydrochloric acid in dioxane (94 μL, 0.38 mmol). The mixture was stirred and heated on a microwave at 175° C. for 40 minutes, then cooled to room temperature. The mixture was neutralized with 0.5M sodium methoxide in methanol. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal dichloromethane, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 minutes, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (110 mg, 0.13 mmol, 71%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ10.27 (s, 1H), 9.20 (brs, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.24 (d, 1H, J=5.13 Hz), 8.07 (d, 1H, J=7.70 Hz), 7.83 (d, 1H, J=7.88 Hz), 7.62 (t, 1H, J=7.70 Hz), 7.34-7.45 (m, 3H), 7.21 (t, 2H, J=8.06 Hz), 6.92-6.99 (m, 1H), 6.65-6.68 (m, 1H), 6.45-6.50 (m, 2H), 3.79 (s, 3H), 3.68-3.75 (m, 2H), 3.19-3.30 (m, 2H), 3.02 (s, 3H), 2.61-2.70 (m, 6H), 2.38-2.46 (m, 6H), 2.26-2.34 (m, 1H), 1.80-1.87 (m, 2H), 1.45-1.56 (m, 2H). MS (ESI): 840 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH3:18].[CH3:19][C:20]1([CH3:35])[C:24]2=[N:25][CH:26]=[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:28]=[C:23]2[NH:22][CH2:21]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH3:19][C:20]1([CH3:35])[C:24]2=[N:25][CH:26]=[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:28]=[C:23]2[N:22]([C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:3]=2[CH3:18])[CH2:21]1
Reactant: Cc1c(-c2ccccc2)nc2ncccc2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: Cc1c(-c2ccccc2)nc2ncccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 4-chloro-3-methyl-2-phenyl-1,8-naphthyridine (60 mg, 0.236 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-6-yl)morpholine (55 mg, 0.236 mmol), sodium tert-butoxide (45.3 mg, 0.471 mmol) and XPhos precatalyst (17.4 mg, 0.024 mmol). Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-methyl-2-phenyl-1,8-naphthyridine. 1H NMR (400 MHz, chloroform-d) δ ppm 9.10 (1H, dd, J=4.1, 2.0 Hz), 8.16 (1H, dd, J=8.4, 2.0 Hz), 7.67-7.77 (2H, m), 7.62 (1H, d, J=2.3 Hz), 7.40-7.57 (4H, m), 5.80 (1H, d, J=2.3 Hz), 3.79-3.90 (2H, m), 3.70-3.77 (4H, m), 2.88-3.07 (4H, m), 2.36 (3H, s), 1.57 (3H, s), 1.52 (3H, s). Mass Spectrum (ESI) m/e=452.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]([F:18])[CH:10]=2)[CH2:4]1.C(N(CC)CC)C.[C:26](SCC)(=[S:28])[CH3:27].CN(C=O)C>C(#N)C>[C:26]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]([F:18])[CH:10]=2)[CH2:4]1)(=[S:28])[CH3:27]
Reactant: CCSC(C)=S
Reactant: NC[C@H]1CN(c2ccc(C(N)=O)c(F)c2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=S)NC[C@H]1CN(c2ccc(C(N)=O)c(F)c2)C(=O)O1

Procedure:
A solution of 5-(S)-aminomethyl-3-[4′-aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one (1.75 g, 6.9 mmol), triethylamine (2.0 ml, 13.8 mmol) and ethyl dithioacetate (0.87 ml, 7.6 mmol) and DMF (5 ml) in acetonitrile (5 ml) was stirred at r.t. for 48 h. Solvent was removed under vacuum, and the crude material purified by silica gel chromatography (eluent: 10% methanol in ethyl acetate). White crystalline solid (1.3 g, 61%). HPLC Rt=4.5 min. MS (m/z): [M+H]+=312.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:22]1[N:27]=[C:26]([Cl:28])[N:25]=[C:24]2[N:29]([CH3:32])[N:30]=[CH:31][C:23]=12>C1COCC1>[C:1]([O:5][C:6](=[O:18])[N:7]([C:22]1[N:27]=[C:26]([Cl:28])[N:25]=[C:24]2[N:29]([CH3:32])[N:30]=[CH:31][C:23]=12)[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(S(C)(=O)=O)cc1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2c(N(C(=O)OC(C)(C)C)c3ccc(S(C)(=O)=O)cc3)nc(Cl)nc21
Temperature: 25 °C

Procedure:
To (4-methanesulfonyl-phenyl)carbamic acid tert-butyl ester (280 mg) in dry THF (3 ml) was added sodium hydride (60% wt suspension in mineral oil, 1.4 equiv., 33.3 mg) at 0° C. After the effervescence ceased, added 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 (113 mg) and the reaction mixture was allowed to warm up to room temperature overnight. DCM/brine extraction gave crude (6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)carbamic acid tert-butyl ester, which was reacted with indazole boronic acid pinacol ester in General Procedure A to give 142 as a beige solid (118 mg). NMR (d6-DMSO): 3.24 (3H, s), 4.15 (3H, s), 7.56 (1H, t), 7.74 (1H, d), 8.01 (2H, d), 8.28 (2H, d), 8.32 (1H, d), 8.41 (1H, s), 8.99 (1H, s), 10.54 (1H, br), 13.25 (1H, br). MS: MH+ 420.13
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][C:12]([C:15](O)=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:25]1([C:31](=[O:39])[CH2:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[CH:19]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:9][C:10]2[S:11][C:12]([C:15]([N:36]3[CH2:37][CH2:38][N:33]([CH2:32][C:31]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:39])[CH2:34][CH2:35]3)=[O:16])=[CH:13][N:14]=2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: O=C(O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCN(C(=O)c2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
2-(3,3-Dicyclohexyl-ureido)-thiazole-5-carboxylic acid (53 mg, 0.15 mmol), 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (42 mg, 0.19 mmol), and HBTU (71 mg, 0.19 mmol) were weighed out and added to a 25 mL reaction flask. DMF (2 mL) and DIEA (65 μL, 0.37 mmol) were added. The reaction was stirred under nitrogen at ambient temperature overnight. The reaction was diluted with EtOAc (10 mL) and quenched with saturated aqueous NH4Cl (10 mL). After separation and extraction with EtOAc (2×5 mL) the combined organic portions were dried over MgSO4. Purification with silica gel chromatography (10% EtOAc and 1% MeOH in CH2Cl2) afforded 17 mg (31%) of the desired compound.
Reaction SMILES: Cl.[CH:2]12[CH2:20][CH:5]([CH:6]([NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][N:12]=3)=[O:10])[CH2:7]1)[CH2:4][NH:3]2.[CH2:21]1[CH:23]([CH:24](O)C#N)[CH2:22]1.C(N(CC)C(C)C)(C)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH:23]1([CH2:24][N:3]2[CH2:4][CH:5]3[CH2:20][CH:2]2[CH2:7][CH:6]3[NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[O:10])[CH2:21][CH2:22]1
Reactant: O=C(NC1CC2CC1CN2)c1n[nH]c2ccccc12
Reactant: N#CC(O)C1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NC1CC2CC1CN2CC1CC1)c1n[nH]c2ccccc12
Temperature: 25 °C
Yield: 50 %

Procedure:
To the suspension of N-(2-azabicyclo[2.2.1]hept-5-yl)-1H-indazole-3-carboxamide hydrochloride (0.36 mmol), cyclopropylcarboxaldehyde (0.9 mmol), and N,N-diisopropylethylamine (1.08 mmol), acetic acid (0.43 mmol) was added sodium triacetoxyborohydride (0.61 mmol). The reaction mixture was maintained at rt for 2 h and was poured into water, extracted with 95/5 dichloromethane/methanol (2×30 mL), and the combined extracts were concentrated. The residue was purified by preparative HPLC, thus providing the product in 50% yield. 1H NMR (CD3OD) δ 8.21 (m, 1H), 7.59 (m, 1H), 7.45 (m, 1H), 7.26 (m, 1H), 4.15 (m, 1H), 3.83 (m, 1H), 3.10 (m, 3H), 2.02 (m, 4H), 1.37 (m, 2H), 0.74 (m, 2H), 0.48 (m, 2H); LC/MS (EI) tR 2.72 min, m/z 311 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8]3[C:11](Cl)=[N:12][C:13]([Cl:15])=[N:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:17][CH2:18][O-:19].[Na+]>C(O)C>[Br:1][C:2]1[C:10]2[NH:9][C:8]3[C:11]([O:19][CH2:18][CH3:17])=[N:12][C:13]([Cl:15])=[N:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(Cl)c2[nH]c3c(Br)cccc3c2n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Cl)nc2c1[nH]c1c(Br)cccc12
Temperature: 25 °C
Yield: 86.1 %

Procedure:
1.0 g (3.2 mmol) 6-bromo-2,4-dichloro-5H-pyrimido[5,4-b]indole was suspended in 5 ml absolute ethanol and mixed with 6 ml (6.4 mmol) 1M sodium ethylate solution (EtOH). The mixture was refluxed for 15 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 0.9 g (86%) 6-bromo-2-chloro-4-ethoxy-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 324, 326 [M−H]−
Reaction SMILES: [CH2:1]1[O:34][C:33]2[CH:32]=[CH:31][C:5]([CH2:6][N:7]([S:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=3[CH3:30])(=[O:20])=[O:19])[C@H:8]([CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:9]([OH:11])=O)=[CH:4][C:3]=2[O:2]1.[CH2:35]([O:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH2:35]([O:42][NH:43][C:9](=[O:11])[C@H:8]([N:7]([CH2:6][C:5]1[CH:31]=[CH:32][C:33]2[O:34][CH2:1][O:2][C:3]=2[CH:4]=1)[S:18]([C:21]1[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=1[CH3:30])(=[O:20])=[O:19])[CH2:12][NH:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)O)c(C)c1
Reactant: NOCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)NOCc2ccccc2)c(C)c1
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a mixture of 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionic acid (1 g, 1.9 mmol), O-benzylhydroxylamine (0.95 ml, 6 mmol) and 1-hydroxybenzotriazole hydrate (370 mg, 1.9 mmol), and N-methylmorpholine (0.7 ml, 5.7 mmol) in anhydrous dimethylformamide (20 ml) was added 1-ethyl-3(3-dimethylamino)-propyl carbodiimide hydrochloride salt. The mixture was stirred overnight and then condensed on the roto-evaporator. The remainder was taken up in ethyl acetate (60 ml) and partitioned with an equal volume of 5% aqueous hydrochloric acid. The ethyl acetate phase was collected and washed consecutively with equal volumes of 5% sodium bicarbonate and brine. The aqueous phases were back extracted with ethyl acetate (2×60 ml) and the organic layers combined, dried with magnesium sulfate, filtered and condensed. The residue was purified by preparative thin layer chromatography using 65% ethyl acetate-hexanes as eluant providing N-benzyloxy 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionamide as a yellow viscous oil (591 mg).