Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH:19]=[CH:18][C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH:25]1[C:20]2[CH:19]=[CH:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[C:15](=[C:12]3[CH2:11][CH2:10][N:9]([CH2:8][CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=4)[CH2:14][CH2:13]3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Product: CCOC(=O)Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 56.7 %

Procedure:
This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and ethyl chloroformate. Yield 56.7%
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br>>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24]
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3cccc(F)c3)C2=O)CC1
Yield: 79 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 3-fluorobenzyl bromide, to give the desired product as a white solid (79%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][N:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[S:28][CH:29]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][N:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[S:28][CH:29]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
23 mg of the crude product from example 29A are dissolved in 0.7 ml of dry DMF, and 11 mg (0.04 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 12 mg (0.14 mmol) of sodium bicarbonate are added. The reaction mixture is stirred at RT for 8 h. The mixture is then poured into 2 ml of saturated aqueous sodium bicarbonate solution, and the aqueous phase is extracted three times with in each case 4 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is removed on a rotary evaporator. The residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[C:25]([N:29]=[C:30]=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:30]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1
Reactant: CC(C)(C)N=C=O
Reactant: Cc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Product: Cc1ccc(C(OC2CN(C(=O)NC(C)(C)C)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-methylbenzhydryloxy]azetidine hydrochloride (151) (0.56 mmol) and tert-butyl isocyanate (0.56 mmol) using the procedure described for compound (10). The desired product was obtained as a colourless glass which gave a white solid on scratching (232 mg, 98%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:5]([C:19]([O:21]C)=[O:20])=[C:6]2[N:11]([C:12]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2>CO>[Br:3][C:4]1[C:5]([C:19]([OH:21])=[O:20])=[C:6]2[N:11]([C:12]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: COC(=O)c1c(Br)c(-c2cccnc2)n2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c(Br)c(-c2cccnc2)n2c1CCCC2
Yield: 89 %

Procedure:
1 cm3 of 5N sodium hydroxide is added with stirring to a solution of 0.34 g of methyl 2-bromo-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate in methanol at 20° C. The orangy solution is heated to reflux for 15 hours. The solvent is then evaporated off at reduced pressure (2.7 kPa) at a temperature close to 40° C. The residue is taken up with 10 cm3 of water and acidified to pH˜3 with 0.2 cm3 of 12N hydrochloric acid and 0.5 cm3 of 1N acetic acid. The precipitate is filtered off, washed with water and then dried in air. 0.29 g of 2-bromo-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid are thus obtained in the form of a cream powder which melts at >260° C., with decomposition.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13])[CH:2]([CH3:4])[CH3:3].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[F:36])[C:30](Cl)=[O:31])#[N:26]>O1CCCC1>[F:36][C:35]1[CH:34]=[CH:33][C:29]([C:30](=[O:31])[CH2:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:14])=[CH:28][C:27]=1[C:25]#[N:26]
Reactant: N#Cc1cc(C(=O)Cl)ccc1F
Reactant: CC(=O)c1ccccc1OCC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)COc1ccccc1C(=O)CC(=O)c1ccc(F)c(C#N)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 68338.9 %

Procedure:
To a solution of 1-(2-isobutoxyphenyl)ethanone (9.0 g, 0.047 mol) in tetrahydrofuran (150 mL) under N2 at −78° C. was added a 1.0 M solution of lithium hexamethyl disilazide in hexanes (100 mL, 2.2 eq) over 5 minutes. The reaction was stirred at −78° C. for 1 h. To the reaction solution was added 3-cyano-4-fluorobenzoyl chloride (8.6 g, 0.047 mmol) in tetrahydrofuran (28 mL) over 5 minutes at −78° C. The reaction mixture was then removed from the dry ice bath and allowed to stir for 1 h. The reaction was quenched with 1N HCl then partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was triturated with acetonitrile and filtered yielding 10.9 g (90%) of 2-fluoro-5-(3-(2-isobutoxyphenyl)-3-oxopropanoyl)benzonitrile and was submitted to the next step without further purification.
Reaction SMILES: [OH:1][CH:2]([CH:21]=[CH2:22])[CH:3]([NH:8][C:9]([C:11]1[C:12]([C:17]([F:20])([F:19])[F:18])=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:10])[C:4](=[O:7])[NH:5][CH3:6].[C:23](O)(=[O:25])[CH3:24].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:23]([O:1][CH:2]([CH:3]([C:4](=[O:7])[NH:5][CH3:6])[NH:8][C:9]([C:11]1[C:12]([C:17]([F:20])([F:19])[F:18])=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:10])[CH:21]=[CH2:22])(=[O:25])[CH3:24]
Reactant: C=CC(O)C(NC(=O)c1cn(C)nc1C(F)(F)F)C(=O)NC
Reactant: CC(=O)O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=CC(OC(C)=O)C(NC(=O)c1cn(C)nc1C(F)(F)F)C(=O)NC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
134 mg (0.42 mmol) of N-(2-hydroxy-1-methylcarbamoylbut-3-enyl)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxamide, 28 mg (0.46 mmol) of acetic acid and 20 mg (0.17 mmol) of dimethylaminopyridine were dissolved in CH2Cl2. At 0° C., 88 mg (0.46 mmol) of 1-(3-dimethylaminopropyl)-3-(ethylcarbodiimide) hydrochloride were added. After 16 h of stirring at RT, the reaction solution was washed and the solvent was removed. This gave 0.10 g (66% of theory) of the title compound as a colorless powder (M+(m/z)=362).
Reaction SMILES: [CH3:1][C:2]1([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C@H:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:16]4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:24]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[O:25]>>[O:22]=[C:14]1[N:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:2]3([CH3:1])[CH2:6][CH2:5][N:4]([C:24]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[O:25])[CH2:3]3)[CH2:8][CH2:9]2)[C@H:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:16]2[NH:15]1
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNC1
Reactant: CC#CCOC(=O)Cl
Product: CC#CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)C1
Yield: 33.9 %

Procedure:
Following the procedure used in example 16 and starting from (3aS,7aS)-3-[1-(3-methylpyrrolidin-3-yl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-one (HCl salt, 0.6 g, 1.75 mmol) and but-2-ynyl chloroformate (0.218 mL, 1.92 mmol), the title compound (0.239 g, 33.9%) was obtained after purification by preparative LC/MS (high pH) as a mixture of diastereomers. MS (M+1): 403.3
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(CC1CC1)c1cncc(Cl)c1
Product: O=C(NCC(CC1CC1)c1cncc(Cl)c1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(5-chloro-pyridin-3-yl)-propylamine. LCMS (MH+): m/z=383.0, tR (minutes, Method D)=0.74
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:6]=1[C:7](OC)=[O:8])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.C1(C)C=CC=CC=1>[OH:8][C:7]1[C:6]2[C:5](=[CH:14][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:12][CH:11]=2)[NH:4][C:1](=[O:3])[CH:2]=1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1NC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=c1cc(O)c2ccc(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.6 %

Procedure:
To a solution of the product of step 2 (3.0 g) in THF (60 ml) was added 0.5 M KHMDS in toluene (108 ml) dropwise at −78° C. After the addition was completed, the mixture was kept at −78° C. for 40 minutes, then it was allowed to warm up slowly at room temperature. The mixture was quenched with H2O and the product was extracted twice with water. The combined aqueous layers were washed with ethyl acetate twice and then acidified with 6N HCl. The solid was filtered and the filter cake was washed with water and dried by vacuum aspiration to get a beige solid which was triturated into ethyl acetate to get a white solid (1.7 g). LRMS (ES+) m/z 230.05 (M+H)+.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1/[CH:6]=[CH:7]/[C:8]([OH:10])=O.Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]2[CH:47]([N:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)[C:42]3=[N:43][CH:44]=[CH:45][CH:46]=[C:41]3[CH2:40][CH2:39][C:38]=2[CH:54]=1.O>CN(C)C=O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]2[CH:47]([N:48]3[CH2:49][CH2:50][N:51]([C:8](=[O:10])/[CH:7]=[CH:6]/[C:2]4[N:3]=[CH:4][NH:5][CH:1]=4)[CH2:52][CH2:53]3)[C:42]3=[N:43][CH:44]=[CH:45][CH:46]=[C:41]3[CH2:40][CH2:39][C:38]=2[CH:54]=1
Reactant: O=C(O)/C=C/c1cnc[nH]1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1c[nH]cn1)N1CCN(C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
To a suspension of urocanic acid (1.38 g; 10.0 mmol) (from Aldrich Chemicals) in N,N-dimethylformamide (175 mL) under an inert atmosphere, was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g; 10.0 mmol) and hydroxybenzotriazole (1.08 g; 8 mmol). The resultant mixture was warmed to 40° C. and stirring continued until all solids dissolved (˜10 min.). To the resultant solution was added 8-chloro-6,11-dihydro-11-(1-piperazinyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (8) (2.51 g; 8.0 mmol), and the resultant solution was allowed to stir at room temperature for 18.5 h. Then water (250 microliters; 13.9 mmol) was added, and the solution was stirred briefly before concentrating under reduced pressure. The residual oil was partitioned between dichloromethane (100 mL) and water (100 mL). The organic extract was dried by filtration through anhydrous magnesium sulfate and solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane-methanol-concentrated ammonium hydroxide (90:9:0.5), to obtain the title compound as a yellow powder that decomposed to a frothy gum at 160° C. SIMS: 434 (MH+; 50%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:18]([CH2:25][CH2:26][CH2:27]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CO>[O:18]([CH2:25][CH2:26][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCCCOc1ccccc1
Reactant: N#Cc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1ccc2[nH]cc(C3CCN(CCCOc4ccccc4)CC3)c2c1
Yield: 44.3 %

Procedure:
A stirred solution of 3-(4-piperidinyl)-5-cyanoindole (0.71 g, 2.2 mmol), 3-phenoxypropyl bromide (0.52 g, 2.4 mmol), and triethylamine (0.6 ml, 4.4 mmol) in methanol (10 mL) was heated at reflux for 18 hours. The solution was concentrated in vacuo. Purification by flash chromatography yielded the product (0.35 g, 44%). 1H-NMR δ(CD3OD) 8.11 (s, 1 H), 7.49 (d, 1 H), 7.40 (d, 1 H), 7.28 (m, 3 H), 6.94 (m, 3 H), 4.12 (t, 2 H), 3.59 (br d, 2 H), 3.26-3.18 (m, 3 H), 3.04 (br t, 2 H), 2.25 (m, 4 H), 2.02 (br q, 2 H).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]([O:33]C)=[O:32])=[CH:23]2.O[CH2:43][CH2:44][CH2:45][NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:35]([CH:30]([CH2:29][C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:19][CH2:43][CH2:44][CH2:45][NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)=[CH:28][CH:27]=2)[C:31]([OH:33])=[O:32])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)C(Cc1ccccc1)Cc1cc2cc(O)ccc2[nH]1
Reactant: OCCCNc1ccccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccccc1)Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.2 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (0.18 g, 0.7 mmol) was added to a solution of methyl 3-(5-hydoxylindolyl)-2-benzylpropanoate (0.12 g, 0.39 mmol), as prepared in the preceding step, 2-(3-hydroxypropyl)aminopyridine (0.07 g, 0.47 mmol), as prepared instep b of Example 1, and tri-n-butylphosphine (0.14 g, 0.7 mmol) in tetrahydrofuran (6.0 mL). After stirring at ambient temperature overnight (16 h), the reaction was concentrated in vacuo and the residue purified by flash chromatography on silica gel (10%-50% ethyl acetate in hexane) to give the title compound as a yellow oil (0.064 g, 38%). 1H-NMR (400 MHz, CDCl3) δ 8.08 (br s, 1H), 7.40 (m, 1H), 7.37 (m, 1H), 7.22 (m, 2H), 7.00 (m, 3H), 6.84 (dd, J=8.9, 2.4 Hz, 1H), 6.54 (m, 1H), 6.40 (d, J=8.4 Hz, 2H), 6.36 (d, J=3.1 Hz, 1H), 4.77 (br s, 1H), 4.40 (m, 1), 4.17 (m, 3H), 3.52 (m, 5H), 3.24 (m, 1), 3.08 (m, 1H), 2.76 (m, 1H), 2.11 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH2:3][CH2:2]1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CC#N>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][CH2:6]1
Reactant: Oc1ccccc1N1CCOCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1N1CCOCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of 2-morpholinophenol (100 mg, 0.56 mmol) and ethyl 2-bromoacetate (200 mg, 0.672 mmol) in CH3CN (10 mL) was added K2CO3 (772.8 mg, 5.6 mmol). The reaction mixture was stirred at 80° C. for 4 h. The solid was removed by filtration and the filtrate concentrated to give a crude material, which was used in the next step without further purification. (130 mg, Yield 90%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C@H:16]2[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])OC(C)(C)C)[CH3:25])[CH2:18][CH2:17]2)[CH:11]=3)[CH2:3][CH2:2]1.Cl.[C:35](OCC)(=O)C>C(OCC)(=O)C>[CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C@H:16]2[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[CH3:35])[CH3:25])[CH2:18][CH2:17]2)[CH:11]=3)[CH2:3][CH2:2]1
Reactant: C[C@@H](CO[C@H]1CC[C@H](n2cc3ccc(OCCC4CC4)cc3n2)CC1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)CO[C@H]1CC[C@H](n2cc3ccc(OCCC4CC4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl [(1S)-2-({trans-4-[6-(2-cyclopropylethoxy)-2H-indazol-2-yl]cyclohexyl}oxy)-1-methylethyl]carbamate (1.2 g) in ethyl acetate (30 mL) was added 4M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in pyridine (10 mL), and acetic anhydride (1 mL) was added thereto at room temperature. The reaction mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate and water, and the solution was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated by HPLC (C18, mobile phase: ammonium hydrogen carbonate aqueous solution/acetonitrile), and water was added to the obtained fraction. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (153 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:24])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 12 h
Yield: 98.9 %

Procedure:
The product from Example 126b (4.0 g, 13.6 mmol) in 40 mL of CH2Cl2 was treated with oxalyl chloride (3.5 g, 27.2 mmol) and DMF (catalytic amount). Mixture was stirred for 12 hours. Mixture was concentrated under vacuum giving the title compound as a yellow oil (4.2 g, 100%).
Reaction SMILES: [N:1]1([C:7]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH:11]([NH2:12])[C:7]2([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:8][CH2:9][CH2:10]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC1(N2CCCCC2)CCC1
Reactant: [Li]c1ccccc1
Product: NC(c1ccccc1)C1(N2CCCCC2)CCC1

Procedure:
The title compound, light yellow liquid, MS: m/e=245.3 [(M+H)+], was prepared in accordance with the general method of intermediate B from 1-piperidin-1-yl-cyclobutanecarbonitrile (intermediate O) and phenyllithium.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](B(O)O)[CH:5]=[CH:4][CH:3]=1.Cl[C:12]1[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=2)[N:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[N:7]=[C:6]([C:12]2[C:21]([N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=3)[N:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1cccc(F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cccc(F)n3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 6-fluoropyridin-2-ylboronic acid (289.0 mg, 2.05 mmol) in dioxane (1 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (300.0 mg, 1.02 mmol), K3PO4 (434.0 mg, 2.05 mmol), and Pd(PPh3)4 (27.6 mg, 0.02 mmol) under nitrogen atmosphere. After stirring 1 h at 90° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.05%-0.2% ethyl acetate in petroleum ether to afford methyl 2-(6-fluoropyridin-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (260.0 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[OH:9])=[CH:6][N:5]=[C:4]2[NH:18][CH:19]=[CH:20][C:3]=12.C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O>[Cl:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]2[NH:18][CH:19]=[CH:20][C:3]=12
Reactant: COc1ccc(C(O)c2cnc3[nH]ccc3c2Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cnc3[nH]ccc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of (4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-methoxyphenyl)methanol (2.34 g, 8.10 mmol, prepared using S from Preparation #1, Step B with (4-(2-methyl-1,3-dioxolan-2-yl)phenyl)magnesium bromide [NOVEL]) and DCM (30 mL) was added Dess-Martin periodinane (3.44 g, 8.10 mmol). The mixture was stirred at rt for about 3 h. Water was added (15 mL) and the resulting precipitate was collected by filtration and dried under reduced pressure at about 60° C. for about 2 h to give (4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-methoxyphenyl)methanone (2.14 g, 92%): LC/MS (Table 2, Method b) Rt=2.17 min.; MS m/z: 287 (M+H)+.