Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(C)ccc4nc3OC)CC2)c1
Yield: 94 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 94%). MS (ESI) m/z 438 (M+1).
Reaction SMILES: [N+:1]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1/[CH:9]=[CH:10]/[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([O-])=O>[Pd].CO>[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1/[CH:10]=[CH:9]/[C:5]1[N:6]=[CH:7][NH:8][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1[nH]cnc1/C=C/c1cccs1
Agent: [Pd]
Solvent: CO
Product: Nc1[nH]cnc1/C=C/c1cccs1
Reaction time: 24 h
Yield: 71.9 %

Procedure:
5% Palladium on carbon (0.5 g) was added to a solution of (E)-5-nitro-4-(2-(thiophen-2-yl)vinyl)-1H-imidazole (4.5 g, 0.02 mol) in methanol (500 mL) and the resulting mixture hydrogenated at atmospheric pressure for 24 hours. The catalyst was removed by filtering through a short bed of Celite™, and the Celite™ washed with 10% MeOH/DCM (200 mL). The filtrate was evaporated to dryness and purified by column chromatography (5-10% MeOH/DCM) to leave the product as a pale brown solid (2.75 g, 71%). δH (DMSO-d6) 11.58 (1H, bs, NH), 7.25 (2H, m), 6.95 (3H, m), 6.62 (1H, d, J=16.0), 4.86 (2H, bs, NH2).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=[CH:12][C@H:11]2[N:28](C)[C@@H:7]1[CH2:8][N:9]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10]2)=[O:5])[CH3:2].Cl[C:38]([O:40][C:41]([CH3:47])([CH3:46])[C:42]([Cl:45])([Cl:44])[Cl:43])=[O:39]>ClCCCl>[Cl:43][C:42]([Cl:45])([Cl:44])[C:41]([O:40][C:38]([N:28]1[C@H:7]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][Si:21]([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:22])[CH3:23])=[CH:18][CH:19]=3)[CH2:12][C@@H:11]1[CH2:10][N:9]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:8]2)=[O:39])([CH3:47])[CH3:46]
Reactant: CCOC(=O)C1C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)=C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Reactant: CC(C)(OC(=O)Cl)C(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Temperature: 60 °C
Yield: 90.2 %

Procedure:
A mixture of compound B9 (6.16 g, 11.9 mmol) and 2,2,2-trichloro-1,1-dimethylethyl chloroformate (3.15 g, 13.1 mmol) in 1,2-dichloroethane (200 mL) was heated to 60° C. for 20 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 8:2) yielded the title compound (7.58 g, 90%). LC-MS: tR=1.29 min, ES+: 707.36.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[S:48]1[CH:52]=[CH:51][CH:50]=[C:49]1[CH2:53][NH2:54]>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:54][CH2:53][C:49]4[S:48][CH:52]=[CH:51][CH:50]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: NCc1cccs1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccs1
Yield: 82 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with thiophen-2-ylmethanamine, the title compound was obtained as a colorless solid in 82% yield: mp 128-131° C.; 1H NMR (300 MHz, CDCl3) δ 7.30-7.20 (m, 3H), 7.06-6.93 (m, 4H), 6.08 (s, 1H), 6.01 (t, J=5.4 Hz, 1 H), 4.73 (d, J=5.4 Hz, 2H), 4.42 (s, 2H), 3.82-3.74 (m, 2H), 3.47-3.39 (m, 2H), 2.49 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.1, 162.4 (d, JC-F=246.4 Hz), 155.8, 142.5, 141.4, 140.9, 131.8 (JC-F=3.1 Hz), 130.0 (JC-F=8.2 Hz), 126.9, 126.1, 125.2, 119.3, 115.7 (JC-F=21.5 Hz), 112.4, 47.4, 42.7, 41.4, 38.5, 16.1; MS (ES+) m/z 452.3 (M+23).
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:12]2[CH:11]=[N:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+]>CC(C)=O>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:1][N:2]=[C:3]2[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[CH2:6][CH2:5][CH2:4]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ON=C1CCCc2ccncc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)ON=C2CCCc3ccncc32)cc1
Temperature: 55 °C
Yield: 66.8 %

Procedure:
To a solution of 8-hydroxyimino-5,6,7,8-tetrahydroisoquinoline (960 mg) and p-toluenesulfonyl chloride (1.69 g) in acetone was added 1N sodium hydroxide (8.88 ml) and the mixture was heated at 55° C. for 2 hours. The acetone was evaporated and the aqueous reaction mixture was extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate and concentrated in vacuo to give 8-(4-methylphenylsulfonyl)oxyimino-5,6,7,8-tetrahydroisoquinoline (1.25 g).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)(=[O:4])[CH2:2][CH3:3].[BH4-].[Na+]>CO>[OH:4][CH:1]([C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)[CH2:2][CH3:3]
Reactant: CCC(=O)c1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(O)c1ccc2c(c1)OCO2
Reaction time: 0.33 h

Procedure:
Into a 250-ml multiple-necked flask were introduced, under nitrogen flow, 30 g of 5-propanoylbenzo[1,3]dioxol (0.268 mol) dissolved in 100 ml of methanol. At 25° C., 7 g of NaBH4 (0.185 mol) dissolved in 50 ml of methanol were dripped in 20 minutes; then the reaction mixture was brought to reflux. After 2 hours the mixture was cooled, the methanol was removed at reduced pressure, and the mixture was diluted with 100 ml of HCl 2M and extracted twice with CH2Cl2. The reunited organic phases were washed with 100 ml of H2O and concentrated at reduced pressure to obtain 30.07 g of dense, clear oil, the analysis of which—GC, MS, NMR (1H, 13C, DEPT)—was in conformity with the desired product. Alternatively, 5-(α-hydroxypropyl)benzo[1,3]dioxol was prepared as follows: Into a 1-litre autoclave, 30 g of 5-propanoylbenzo[1,3]dioxol (0.168 mol) dissolved in 150 ml of isopropanol and 1 g of Ru/C 5% were poured. The autoclave was closed, rendered inert with nitrogen, and brought to the pressure of 1 bar with H2 under stirring. The mixture was left under stirring with H2 pressure constant at 1 bar for 1 hour; then it was washed with N2 and filtered. By evaporation of the solvent at reduced pressure, 30 g of a dense oil were obtained, the analysis of which—GC, MS, NMR (1H,13C, DEPT)—was in conformity with the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([CH3:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[CH3:30][C:31]([CH3:33])=O.C([BH3-])#N.[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([CH3:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][N:25]([CH:31]([CH3:33])[CH3:30])[CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1C1CNC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1C1CN(C(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a mixture of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-3-ethoxy-6-methylbenzonitrile (70 mg, 0.2 mmol) in methanol (50 mL) was added acetone (0.1 mL, 2 mmol) and sodium cyanoborohydride (17 mg, 0.27 mmol). The reaction was stirred at room temperature for 1 h, and was complete by LC/MS. The reaction was quenched with water and was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the crude product. The product was purified by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the title compound as a white amorphous solid (0.030 g, 40%). The product was isolated as a racemic mixture. LCMS calculated for C24H32N7O(M+H)+: m/z=434.2; found: 434.3. 1H NMR (300 MHz, CD3OD) δ 8.17 (s, 1H), 7.35 (s, 1H), 6.37 (q, J=7.1 Hz, 1H), 4.17-3.98 (m, 4H), 3.90-3.71 (m, 3H), 2.65 (s, 3H), 2.46 (s, 4H), 1.84 (d, J=7.1 Hz, 3H), 1.42 (t, J=7.0 Hz, 3H), 1.03 (dd, J=6.2, 1.4 Hz, 6H).
Reaction SMILES: C([O:3][C:4](=[O:23])/[CH:5]=[C:6](\[CH3:22])/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16](C)[O:15][C:14]=1[CH3:20])C.[OH-].[K+:25].O>CO>[CH3:22]/[C:6](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[CH:16][O:15][C:14]=1[CH3:20])=[CH:5]\[C:4]([O-:23])=[O:3].[K+:25]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)oc(C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(/C=C/c1c(C)coc1C)=C\C=C\C(C)=C\C(=O)[O-]

Procedure:
(E,E,E,E)-3,7-dimethyl-9-(2,4,5-trimethyl-3-furyl)-2,4,6,8-nonatetraenoic acid ethyl ester (16 g.) was dissolved in methanol (100 ml.) containing potassium hydroxide (10 g.) and water (20 ml.) and the resulting mixture was heated at reflux for 1 hour. On cooling, a potassium salt crystallized out. This was filtered off, washed with methanol and crystallized from isopropanol-water to give pure potassium (E,E,E,E)-3,7-dimethyl-9-(2,4-dimethyl-3-furyl)-2,4,6,8-nonatetraenoate, m.p. 265°-70° (dec.).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[C:8](OC(=O)C)(=[O:10])[CH3:9]>>[C:8]([NH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])(=[O:10])[CH3:9]
Reactant: CCC(N)C(=O)O
Reactant: CC(=O)OC(C)=O
Product: CCC(NC(C)=O)C(=O)O

Procedure:
163 g (1.58 mol) of 2-aminobutyric acid are reacted analogously to Example 1A with 242 g (2.37 mol) of acetic anhydride to give 2-(acetylamino)butanoic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:28]=[CH:27][C:19]3[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=3[CH:17]=2)=[CH:12][C:11]=1[NH:29][CH:30]([CH3:32])[CH3:31]>CS(C)=O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:28]=[CH:27][C:19]3[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=3[CH:17]=2)=[CH:12][C:11]=1[NH:29][CH:30]([CH3:32])[CH3:31]
Reactant: CN(C)CCO
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NC(C)C)c3)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3cnc(OCCN(C)C)c(NC(C)C)c3)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.5 %

Procedure:
2-(dimethylamino)ethanol (140.2 mg, 1.573 mmol) was dissolved in DMSO (1.5 ml) and sodium hydride (85.8 mg, 60% in mineral oil, 2.15 mmol) was added. The reaction was stirred under nitrogen at room temperature for almost 2 hours, and then N-(6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (102.5 mg, 0.2840 mmol) was added. The flask was put in a preheated oil bath (105° C.) and stirred under nitrogen (a reflux condenser was added after about 5 minutes). After 90 minutes, the reaction was cooled to room temperature and quenched with water. The reaction was extracted with 10:1 DCM/MeOH, but the product is water soluble, so the organic and aqueous phases were combined, concentrated, and filtered through a pad of Celite® (diatomaceous earth), which was washed with DCM and MeOH. This filtrate was concentrated and purified on a silica gel column (20:1 DCM/MeOH to 15:1 DCM/2 N ammonia in MeOH to 10:1 DCM/2 N ammonia in MeOH) to afford N-(6-(6-(2-(dimethylamino)ethoxy)-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (39.4 mg, 34% yield). MS (ESI pos. ion) m/z: 414. Calculated exact mass for C21H27N5O2S 413.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH:33][CH3:34])[CH2:27][CH2:26]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C(=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2[NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][N:33]([CH3:34])[C:2]3[S:3][CH:4]=[CH:5][N:6]=3)[CH2:27][CH2:26]2)=[CH:10][CH:9]=1
Reactant: Brc1nccs1
Reactant: CNCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CN(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1nccs1
Temperature: 140 °C
Yield: 50 %

Procedure:
A mixture of 2.5 parts of 2-bromothiazole, 5.72 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(methylamino)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine, 1.6 parts of sodium carbonate, 0.1 parts of potassium iodide and 27 parts of N,N-dimethylacetamide was stirred and heated overnight at 140° C. The reaction mixture was poured onto water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane, yielding 3.5 parts (50%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[methyl(2-thiazolyl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 143.2° C. (compound 50).
Reaction SMILES: [Cr:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Cr:6]([O-])([O-:9])(=[O:8])=[O:7].[Na+:11].[Na+].S(=O)(=O)(O)O>>[Cr:1]([O:5][Cr:6]([O-:9])(=[O:8])=[O:7])([O-:4])(=[O:3])=[O:2].[Na+:11].[Na+:11]
Reactant: O=[Cr](=O)([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]

Procedure:
If the concentrated chromate phase is sodium chromate, this solid phase may be acidified by, e.g., sulfuric acid either before or after evaporation to provide a sodium dichromate product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:12]([C@H:14]1[O:16][CH2:15]1)Cl.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[NH2:11][CH2:10][C@:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:12][C@@H:14]1[CH2:15][OH:16]
Reactant: ClC[C@@H]1CO1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: NC[C@]1(c2ccc(Cl)c(Cl)c2)C[C@@H]1CO
Temperature: -15 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 2-(3,4-Dichlorophenyl)acetonitrile (3.5 g, 18.81 mmol) and (S)-(+)-Epichlorohydrin (1.877 ml, 23.99 mmol) in tetrahydrofuran (18.5 mL) at −15° C. (dry ice/ethanol/water bath, internal temp monitored with thermocouple) under atmosphere of N2 was added sodium bis(trimethylsilyl)amide (16.5 mL, 33.0 mmol) dropwise over 3 hours. The reaction mixture was stirred for additional 3 hours at −15° C., then, overnight at 4° C. (cold room). The mixture was cooled to −5° C. and borane-methyl sulfide complex (4.4 mL, 44.0 mmol) was added over 2 hours via syringe pump. The reaction mixture was then gradually warmed to 40° C. over 3 hours. After aging 1.5 hours at 40° C., the reaction mixture was cooled to 20-25° C. and slowly quenched into a 2N HCl solution (27.7 L). The quenched mixture was then stirred for 1 h at 40° C. Ammonium hydroxide concentrated (6.3 L) was added and the aqueous layer was discarded. i-PrOAc (18.5 L) and 5% dibasic sodium phosphate (18.5 L) were charged. The organic phase was then washed with saturated brine (18.5 L), dried over magnesium sulfate, filtered and evaporated to afford title compound 487 (4.63 g, 100%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[C:10]([CH3:18])=[C:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:36]3[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)[CH:15]=2)[C:10]([CH3:18])=[C:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(Br)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2ccc3c(C)c(-c4ccccc4)n(Cc4ccccc4)c3c2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 3 of example 3. Thus, 1-benzyl-6-bromo-3-methyl-2-phenyl-1H-indole (1.432 g, 3.805 mmol) was reacted with aqueous 2M K2CO3 (3.8 ml), 4-methoxyphenylboronic acid (0.809 g, 5.327 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.093 g, 0.114 mmol) in dioxane (38 ml) to give the product (1.017 g, 2.861 mmol, 75%) as a white solid, mp 142-145° C. 1H NMR (DMSO-d6) δ 2.23 (s, 3H), 3.77 (s, 3H), 5.39 (s, 2H), 6.86 (d, J=7.0 Hz, 2H), 6.98 (d, J=8.9 Hz, 2H), 7.13 (t, J=7.3 Hz, 1H), 7.18 (t, J=7.0 Hz, 2H), 7.34 (dd, J=1.5, 7.8 Hz, 1H), 7.38-7.44 (m, 3H), 7.48 (t, J=7.0 Hz, 2H), 7.55-7.61 (m, 4H); [ESI(+)], m/z 404 (M+H)+.
Reaction SMILES: BrC1C=C(C=CC=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[NH:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]1C(O)=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:55]3[NH:54][C:62]4[C:57]([CH:56]=3)=[CH:58][CH:59]=[CH:60][CH:61]=4)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:18]=[C:19]([O:27][CH3:28])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cc4ccccc4[nH]3)nn2)cc(OC)c1OC
Yield: 79 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 1H-indole-2-carboxylic acid (136 mg, 0.85 mmol), diisopropylethyl-amine (0.33 mL, 1.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (360 mg, 0.94 mmol) in dimethylformamide (5 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-indole-2-carboxamide (232 mg, 79%) as a yellow solid. MS m/z 448 (M+1).
Reaction SMILES: [CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21](O)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[NH:25]1[CH2:28][CH2:27][CH2:26]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([N:25]3[CH2:28][CH2:27][CH2:26]3)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Reactant: C1CNC1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 84 h
Yield: 94.6 %

Procedure:
A mixture of 5-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 213 μmol), azetidine (71.6 μl, 1.07 mmol), propylphosphonic anhydride (50% in ethyl acetate, 314 μl, 533 μmol) and diisopropylethylamine (112 μl, 640 μmol) in tetrahydrofuran (4 ml) was stirred for 3.5 days (weekend) at 25° C. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (74 mg, 94.5%) as a white solid. mp: 226-227° C., MS: m/z=366.1 (M−H+)
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([F:14])[CH2:13][O:12][CH2:11]2)[CH:5]=1.[OH-].[Na+]>CO>[F:14][C:10]1([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:15])=[O:2])[CH2:11][O:12][CH2:13]1
Reactant: COC(=O)c1cccc(C2(F)COC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(C2(F)COC2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
200 mg (0.951 mmol) 3-(3-fluoro-oxetan-3-yl)-benzoic acid methyl ester was dissolved in 10 mL MeOH and treated with 0.40 mL 4 M aqueous NaOH solution at RT over the weekend. 0.20 mL 4 M aqueous NaOH solution was added and the mixture was stirred at 50° C. for 2 h. The reaction mixture was concentrated, acidified with 4 M aqueous hydrochlorid acid and stirred for 30 min at 0° C. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:22]1[C:23]2[CH2:30][CH2:29][CH2:28][C:24]=2[N:25]=[CH:26][N:27]=1.Cl.C[O-].[Na+]>C(Cl)(Cl)Cl>[N:25]1[C:24]2[CH2:28][CH2:29][CH2:30][C:23]=2[C:22]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([C:12](=[O:13])[CH2:11][CH2:10][CH:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)=[CH:15][CH:16]=2)=[N:27][CH:26]=1
Reactant: Clc1ncnc2c1CCC2
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc(N)cc2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC(CCC(=O)c2ccc(Nc3ncnc4c3CCC4)cc2)CC1
Yield: 95.1 %

Procedure:
To 80 ml of chloroform were added 4.53 g of 4-[3-(1-acetylpiperidin-4-yl)propanoyl]aniline and 3.83 g of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and after adding 10 ml of a chloroform solution of hydrochloric acid (containing 0.9 g of hydrochloric acid), the mixture was refluxed under heating for 5 hours. After completion of the reaction, a 28% sodium methoxide was added to the mixture under ice cooling to make it alkaline and then the solvent was removed by distillation under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 6.16 g of the title compound as brown powder.