Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].CO.[C:4]1([C:10]2[N:11]=[C:12]([C:21]3[CH:22]([CH2:27][C:28]4[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:24][CH2:25][CH:26]=3)[O:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.CCOC(C)=O>[C:4]1([C:10]2[N:11]=[C:12]([C:21]3[CH:22]([CH2:27][C:28]4[CH:29]=[C:30]([S:34]([NH2:1])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:24][CH2:25][CH:26]=3)[O:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a mixture of 28% ammonia solution (0.7 ml) and MeOH (1.0 ml) was added a solution of crude 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-benzenesulfonyl chloride (253 mg, 0.52 mmol) in tetrahydrofuran (3 ml) at 5° C. After stirring at room temperature for 30 min, the reaction mixture was diluted with EtOAc, washed with 1N hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 2:1 elution) to give 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzenesulfonamide (41.3 mg, 17%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([OH:26])[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3].Cl[C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:25]=[C:24]([O:26][C:30]2[N:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)[CH:23]=[C:13]([C:14]([NH:16][C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)=[O:15])[CH:12]=1)[CH3:9])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)Nc3ccn(C)n3)c2)nc1
Yield: 73.2 %

Procedure:
A solution of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (1.00 g, 2.47 mmol), methyl 6-chloronicotinate (0.450 g, 2.60 mmol), and cesium carbonate (1.204 g, 3.71 mmol) in acetonitrile (15 mL) was heated at 160° C. using microwave heating for 90 minutes. The acetonitrile was removed in vacuo and the residual oil partitioned between water (50 mL) and ethyl acetate (75 mL). The ethyl acetate layer was separated, washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (0.977 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:27]([O:31][C:32](=[O:36])[CH2:33][O:34][NH2:35])([CH3:30])([CH3:29])[CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:27]([O:31][C:32](=[O:36])[CH2:33][O:34]/[N:35]=[CH:18]/[C:17]1[CH:20]=[CH:21][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:23]([F:26])([F:24])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[CH3:22])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CON
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1/C=N/OCC(=O)OC(C)(C)C
Yield: 56 %

Procedure:
A mixture of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde (i.e. the product of Step 1, Example 1, 1.00 g), amino-oxyacetic-acid-tert-butyl-ester (403 mg), p-toluene sulfonic acid (43 mg) and toluene (20 mL) were heated to reflux for 30 min. After cooling, the mixture was washed with water, and the organic layer was dried over Na2SO4. After evaporation the residue was purified by flash chromatography on silica gel to yield the title compound (745 mg, 56%)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13].[OH:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])[O:15][CH2:16][CH2:17][OH:18]
Reactant: OCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCO)cc1OCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 2-(2-chloroethoxy)-4-fluoro-1-nitro-benzene (91.3 g, 6 mmoles), 2-hydroxyethanol (0.57 g, 7.2 mmoles), and cesium carbonate (2.34 g, 7.2 mmoles) in DMF were stirred together at room temperature for 1 hour, diluted with water and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum to afford the title compound (0.63 g, 2.4 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:6]2[O:7][CH2:8][C@H:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:5]2=[CH:4][CH:3]=1.NC1C(C(OC)=O)=C(OC[C@@H]2CCCN2)C(Br)=CC=1>>[NH2:1][C:2]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:6]2[O:7][CH2:8][C@@H:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc2c1OC[C@H]1CCCN21
Agent: COC(=O)c1c(N)ccc(Br)c1OC[C@@H]1CCCN1
Product: COC(=O)c1c(N)ccc2c1OC[C@@H]1CCCN21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 6, starting from methyl 6-amino-3-bromo-2-((S)-1-pyrrolidin-2-ylmethoxy)benzoate (Intermediate 14).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]=[CH2:11].[Li]CCCC.CN(C)[CH:19]=[O:20]>C1COCC1>[CH2:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:19]=[O:20])[CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCc1ccccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCc1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a mixture of 1-bromo-2-(but-3-en-1-yl)benzene (1 g, 4.74 mmol) in THF (15 mL) at −78° C. was added BuLi (2.274 mL, 5.68 mmol) dropwise. It was stirred at this temperature for 1 h, then N,N-dimethylformamide (0.416 g, 5.68 mmol) was added and stirred at −78° C. for 30 min. then warmed up to rt and stirred at rt for 1 h. It was then quenched with NH4Cl, extracted with ether. The organic layer was then dried over MgSO4, filtered and concentrated to obtain 2-(but-3-en-1-yl)benzaldehyde (0.7 g, 92%) as an oil. 1H NMR (400 MHz, CDCl3) δ 10.35-10.26 (m, 1H), 7.86 (dd, J=7.6, 1.5 Hz, 1H), 7.54 (td, J=7.5, 1.6 Hz, 1H), 7.44-7.38 (m, 1H), 7.30 (d, J=8.1 Hz, 1H), 5.95-5.83 (m, 1H), 5.09-5.00 (m, 2H),), 3.20-3.12 (m, 2H), 2.44-2.36 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH:22]=[CH2:23]>>[CH2:23]([N:15]1[CH2:16][CH2:17][O:18][CH:13]([CH2:12][NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH2:14]1)[CH2:22][CH:21]=[CH2:20]
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Reactant: C=CCCBr
Product: C=CCCN1CCOC(CNC(=O)Nc2ccc(Cl)cc2)C1

Procedure:
Example 27 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 4-bromobut-1-ene (4.1 μl) to give the title compound (0.0027 g).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[N:24]1([C:28]2[O:32][N:31]=[C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([N+:40]([O-])=O)[CH:34]=3)[N:29]=2)[CH2:27][CH2:26][CH2:25]1>ClCCl.N1C=CC=CC=1>[N:24]1([C:28]2[O:32][N:31]=[C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([NH:40][C:10]([C:3]4[N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1][CH:2]=4)=[O:12])[CH:34]=3)[N:29]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(-c2noc(N3CCC3)n2)cc1[N+](=O)[O-]
Reactant: O=C(O)c1cnc2ccccn12
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-c2noc(N3CCC3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (71 mg, 0.39 mmol) in anhydrous dichloromethane (2 mL) was added dropwise oxalyl chloride (173 uL, 1.98 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was concentrated. A stirring mixture of the acid chloride and 5-(azetidin-1-yl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (109) (85 mg, 0.29 mmol) in anhydrous pyridine (2 mL) was stirred at room temperature for 30 minutes. The crude product was purified on silica gel using 10% MeOH in dichloromethane to give N-(5-(5-(azetidin-1-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F77). 1H NMR (400 MHz, CD2Cl2) δ 10.10 (s, 1H), 9.51-9.48 (m, 1H), 8.65 (s, 1H), 7.94 (d, J=1.6 Hz, 1H), 7.86-7.83 (m, 1H), 7.71 (dd, J=1.6, 7.6 Hz, 1H), 7.64-7.60 (m, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.27-7.24 (m, 1H), 4.26-4.22 (m, 4H), 2.48-2.40 (m, 2H), 2.34 (s, 3H). MS m/z 374.15 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:26])=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[Cl:25][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:4]([F:26])[CH:5]=1
Reactant: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F
Yield: 44.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-70, 0.080 g, 0.206 mmol), pivaloyl chloride (0.027 g, 0.227 mmol), THF (5.0 mL) and TEA (0.2 mL) to afford 0.043 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.13 (s, 9H), 4.31-4.32 (m, 2H), 7.86 (d, J=6.5 Hz, 2H), 8.13-8.18 (m, 3H), 12.70 (s, 1H); MS (m/z): 471.14 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].C(N(CC)CC)C.[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[CH:32]=1)[C:27](Cl)=[O:28])([O-:23])=[O:22]>CN(C=O)C.O1CCOCC1>[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[CH:32]=1)[C:27]([N:2]([CH3:1])[CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5])=[O:28])([O-:23])=[O:22]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
N-Methylglucamine (21.4 g, 0.11 mol) was suspended in DMF (200 ml). Triethylamine (11.5 g, 0.11 mol) was added. To this suspension was at 4° added by stirring 3,5-dinitrobenzoyl chloride (23.0 g, 0.1 mol) dissolved in dioxane (100 ml). The temperature rose to 10°. The stirring was continued at this temperature for 2 hours followed by 16 hours at room temperature. Triethylamine hydrochloride was filtered off and the DMF distilled off from the filtrate. The residue, a pale brown oil, was dissolved in water (200 ml), the pH adjusted to 1 and the solution extracted with phenol according to standard procedure. The final aqueous solution was treated with charcoal at room temperature for 24 hours and the filtrate evaporated to dryness in vacuo. The residue -- a pale brown oil -- was further dried in vacuo at 65°. Yield: 25.5 g (65%). The IR-spectrum showed a characteristic carbonyl absorption band at 1670 -- 1620 cm -1. Rf value: 0.55 - 0.6 (paper, n-BuOH: EtOH: NH3 : H2O= 4 : 1 : 2 : 1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[CH:4]=[CH:3][CH:2]=1.[Na]>C(O)C>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc2cccnc12
Agent: [Na]
Solvent: CCO
Product: Nc1cccc2c1NCCC2
Temperature: 70 °C
Yield: 139.7 %

Procedure:
25 g (0.169 mol) of quinolin-8-amine are dissolved in 600 ml of ethanol. The reaction mixture is heated to 70° C. and 45 g of sodium are added in small pieces. The mixture is brought to the reflux temperature until the sodium has disappeared. The mixture is then evaporated to dryness and the residue is taken up in an ether/hexane (50/50) mixture, filtered and again evaporated to dryness. 35 g of product are obtained in the form of an oil which is used as is in the following stage.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][S:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=1)[CH3:2].[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([Cl:32])=[CH:34][CH:35]=3)=[CH:17][C:16]=2[CH2:22][S:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CSCc2ccccc2)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSCc2ccccc2)c1

Procedure:
As described for Example 10, [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and benzyl mercaptan were reacted to provide [3-(2-benzylsulfanylmethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester, which was reduced to [3-(4-amino-2-benzylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and then treated with 4-chlorobenzoyl chloride to provide {3-[2-benzylsulfanylmethyl-4-(4-chloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided Compound 18.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[N:3][C:2]=1[NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14].[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(Cl)Cl>O>[Si:20]([O:14][CH2:13][C@@H:12]([NH:11][C:2]1[N:3]=[CH:4][C:5]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[N:1]=1)[CH3:15])([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](CO)Nc1ncc2c(n1)CNCC2
Solvent: ClCCl
Solvent: O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1ncc2c(n1)CNCC2
Yield: 66.2 %

Procedure:
A solution of (S)-2-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-ylamino)propan-1-ol (138, 0.215 g, 1.03 mmol), TBDMS-Cl (0.171 g, 1.14 mmol) and TEA (0.216 ml, 1.55 mmol) and DCM (5 mL) were stirred for 18 h, poured into water and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by SiO2 chromatography eluting with DCM/MeOH (500:50) to afford 0.220 g (66.1%) of (S)—N-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine (152).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:8]=[C:9]2[C:13]=1[N:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[N:11]=[CH:10]2)(=O)C.C([O-])([O-])=O.[K+].[K+]>CCO>[OH:4][C:5]1[CH:6]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:8]=[C:9]2[C:13]=1[N:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[N:11]=[CH:10]2
Reactant: CCOC(=O)c1cc(OC(C)=O)c2c(cnn2C2CCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc(O)c2c(cnn2C2CCCCO2)c1
Yield: 76.5 %

Procedure:
Ethyl 7-(acetyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (6 g, 0.018 mol) was dissolved in EtOH (100 mL) and K2CO3 (7 g, 0.05 mol) was added. The reaction mixture was heated at reflux over a period of 6 hours and evaporated. The residue was treated with water (150 mL), and the product was extracted with EtOAc (3×50 mL). The combined extracts were evaporated and the residue was purified by chromatography (EtOAc/hexane, 1:4) to afford ethyl 7-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (4 g, 85%).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][NH:29]1>>[CH2:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][N:29]1[C:11]([C:10]1[CH:9]=[C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=2)[CH:16]=[C:15]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)[CH:14]=1)=[O:13]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: c1ccc2c(c1)CCNC2
Product: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCc4ccccc4C3)c2)cc1
Yield: 85.2 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.8 g (2.24 mmol) and 1,2,3,4-tetrahydro-isoquinoline (0.3 g, 2.26 mmol) were used to afford 0.9 g of the required product. 1H NMR (DMSO-d6): δ 2.82 (2H, m), 3.58 (1H, m), 3.80 (1H, m), 4.08 (1H, m), 4.74 (1H, m), 7.10 (3H, m), 7.20 (4H, m), 7.28 (4H, d), 7.90 (2H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]([Cl:13])[C:3]=1[C:4]([OH:6])=O.ON1C2N=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[NH:66]1[C:74]2[CH:73]=[CH:72][N:71]=[C:70]([NH:75][C:76]([CH:78]3[CH2:80][CH2:79]3)=[O:77])[C:69]=2[CH:68]=[CH:67]1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CC=CC=1.O>[Cl:13][C:7]1[CH:8]=[C:9]([CH2:11][OH:12])[CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([N:66]1[C:74]2[CH:73]=[CH:72][N:71]=[C:70]([NH:75][C:76]([CH:78]3[CH2:79][CH2:80]3)=[O:77])[C:69]=2[CH:68]=[CH:67]1)=[O:6]
Reactant: O=C(Nc1nccc2[nH]ccc12)C1CC1
Reactant: O=C(O)c1c(Cl)cc(CO)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: C[NH3+]
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(CO)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 11.2 %

Procedure:
To a stirred solution of 2,6-dichloro-4-(hydroxymethyl)benzoic acid (219 mg, 0.99 mmol), 1-hydroxy-7-azabenzotriazole (202 mg, 1.48 mmol), dimethylaminopyridine (60 mg, 0.49 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (567 mg, 1.48 mmol) in N,N-dimethylaniline, N-(1H-pyrrolo[3,2-c]pyridin-4-yl)cyclopropanecarboxamide (200 mg, 0.99 mmol) was added followed by N,N-diisopropylethylamine (0.25 ml, 1.48 mmol). The reaction mixture was stirred at room temperature for 15 hours. The contents were diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography using methanol in dichloromethane (3%) as eluent to yield N-{1-[2,6-dichloro-4-(hydroxymethyl)benzoyl]-1H-pyrrolo[3,2-c]pyridin-4-yl}cyclopropanecarboxamide (45 mg, 11°/o).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][CH:34]([OH:36])C)N>>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[C:4]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:15][CH:14]=3)=[N:3][N:2]([CH2:1][CH:34]([OH:36])[CH3:33])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: CC(O)CNN
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: CC(O)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-hydrazino-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.44 (bs, 2 H), 8.20 (d, J=8.3 Hz, 1 H), 8.08 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.3 Hz, 1 H), 7.75 (m 2H), 7.67 (d, J=8.3 Hz, 1H), 7.56 (t, J=8.3 Hz, 1H), 7.36 (d, J=8.7 Hz, 2H) 7.30 (m, 2H), 7.03 (d, J=9.1 Hz, 2 H), 5.40 (s, 2H), 4.49 (m, 1H), 4.23 (m, 1H), 4.02 (m, 1H), 1.83 (m, 1H), 1.28 (d, J=6.2 Hz, 3H); MS: (M+H m/z=437.2).
Reaction SMILES: C[Mg]Br.[F:4][C:5]([F:10])([F:9])[C:6]([OH:8])=[O:7].[Cl:11][C:12]1[N:13]=[CH:14][N:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:41]=[C:27]4[CH:28]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)[CH2:29][C:30](=[O:33])[CH2:31][CH2:32][N:26]4[N:25]=3)=[CH:19][C:18]=2[O:42][CH3:43])[CH:16]=1.[C:44](O)(C(F)(F)F)=O>C1COCC1.[Cu]I>[F:4][C:5]([F:10])([F:9])[C:6]([OH:8])=[O:7].[Cl:11][C:12]1[N:13]=[CH:14][N:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:41]=[C:27]4[C@@H:28]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)[CH2:29][C@@:30]([CH3:44])([OH:33])[CH2:31][CH2:32][N:26]4[N:25]=3)=[CH:19][C:18]=2[O:42][CH3:43])[CH:16]=1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: [Cu]I
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3n(n2)CC[C@](C)(O)C[C@@H]3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 17 %

Procedure:
A 25 mL round bottom flask was charged with copper (I) iodide (8.16 mg, 0.043 mmol) in THF (1 mL), and cooled to 0° C. A solution of methylmagnesium bromide (1.53 mL, 2.142 mmol, 1.4 M in THF) was added dropwise to the stirred solution and stirred for 20 min. To solution of methyl cuprate was added 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (100 mg, 0.214 mmol, from example 137) in THF (1 mL) and the reaction was stirred at 0° C. for an additional 2 h. The resulting mixture was quenched slowly with saturated ammonium chloride, and the aqueous layer was washed with EtOAc (×3). The combined organic layers were then washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (21.6 mg, 17% yield) as a TFA salt. LC-MS (M+H)+ 483.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 10.36 (1 H, br. s.), 9.30 (1 H, br. s.), 8.05 (1 H, s), 7.22-7.33 (2 H, m), 7.08-7.20 (6 H, m), 4.62-4.76 (2 H, m), 4.34-4.46 (1 H, m), 3.82-3.92 (3 H, m), 2.16-2.34 (2 H, m), 2.04-2.14 (1 H, m), 1.92-2.04 (1 H, m), 1.43-1.53 (3 H, m).