Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1ccc(OC)cc1
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: COc1ccc(C#Cc2cnc3cc(C(C)(C)C)nn3c2)cc1

Procedure:
The title compound, yellow solid, MS: m/e=306.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-4-methoxybenzene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([OH:15])=O)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=1)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:42]([O:49][C:50](=[O:56])[C@@H:51]1[CH2:55][CH2:54][CH2:53][NH:52]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.C(Cl)CCl>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:52]2[CH2:53][CH2:54][CH2:55][C@H:51]2[C:50]([O:49][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:56])=[O:15])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCOC(=O)c1cc(OCC(=O)O)n(-c2ccccc2)n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)n(-c2ccccc2)n1
Reaction time: 16 h

Procedure:
To a solution of 9.5 g 5-carboxymethoxy-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 100 ml DMF were added 5.0 g HOBt, 6.3 g EDC and 10.9 ml DIPEA. After 5 minutes 7.9 g L-proline benzyl ester hydrochloride were added and the resulting solution stirred for 16 h. The reaction mixture was concentrated, dissolved in dichloromethane and extracted with aqueous LiCl (4%) and saturated NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using ethyl acetate/heptane 1:1 as eluent. Yield: 13.2 g colorless foam.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([C:16]#[N:17])[CH:7]2[C:14]#[N:15].CC([O-])=O.[Na+]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][CH:2]=[C:3]2[C:8]=1[CH:7]([C:14]#[N:15])[CH:6]([C:16]#[N:17])[CH2:5][CH2:4]2
Reactant: COc1ccc(Br)c2c1C(C#N)C(C#N)CC2
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1cccc2c1C(C#N)C(C#N)CC2
Yield: 85.1 %

Procedure:
The product from Example 53 (2.90 g) was treated with 3.0 g 10% Pd/BaSO4 and 1.36 g NaOAc in 250 ml methanol and hydrogenated at 4 atm for 4 h. The reaction was filtered and evaporated; and the product was dissolved in ethyl acetate, washed with 5% NaHCO3, dried (MgSO4), and evaporated to yield 1.80 g of the desired product as a colorless oil. NMR (CDCl3) δ 2.30 (m, 2H), 2.80-3.20 (m, 3H), 3.91 (s, 3H), 4.39 (d, 1/3H), 4.46 (d, 2/3H), 6.87 (m, 2H), 7.27 (m, 1H).
Reaction SMILES: C=O.[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][NH2:21])[CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:24][NH:21][O:20][CH:17]1[CH2:16][CH2:15][N:14]([S:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:3])([F:22])[F:23])[CH:6]=2)(=[O:13])=[O:12])[CH2:19][CH2:18]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CNOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Formaldehyde (166 mg, 5.55 mmol) was added to a solution of O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl) hydroxylamine (200 mg, 0.617 mmol) in 1,2-dichlorethane (5 ml) and stirred at room temperature for 3 hours. Sodium triacetoxyborohydride was added and stirred at room temperature for 12 hours. The reaction mixture was diluted with of ethyl acetate (30 ml), washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (the residue was purified by preparative TLC (ethyl acetate/petroleum ether: 67/33) to give N-methyl-O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (125 mg, 60%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(C(C)C)CC)(C)C.Cl[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1.C(OCC)(=O)C>O1CCCC1>[O:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Clc1nc2ccccc2o1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cccc(CCNc2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Ethyl 2-[3-(2-aminoethyl)phenoxy]-2-methylpropionate (1.1 g, 4.38 mmol) was dissolved in tetrahydrofuran (22 mL). Subsequently, diisopropylethylamine (1.14 mL, 6.57 mmol) and then 2-chlorobenzoxazole (611 mL, 5.26 mmol) were added thereto, and the mixture was stirred under argon atmosphere for 14 hours at room temperature. Ethyl acetate was added to the reaction mixture. Washing was performed sequentially with water and saturated brine, followed by drying over sodium sulfate. Thereafter, the reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=10/1), whereby the target compound was obtained (900 mg, 2.44 mmol, 55.8%).
Reaction SMILES: C1([C@H]([NH:9][C@H:10]([CH3:25])[CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([O:23][CH3:24])=[O:22])=[CH:15]3)C)C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:9][C@H:10]([CH3:25])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([O:23][CH3:24])=[O:22])=[CH:15]2
Reactant: COC(=O)c1cc2cc(C[C@@H](C)N[C@H](C)c3ccccc3)ccc2[nH]1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1cc2cc(C[C@@H](C)N)ccc2[nH]1
Temperature: 25 °C
Yield: 107.6 %

Procedure:
A solution of methyl 5-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl)-1H-indole-2-carboxylate (Preparation 15, 9.34 g, 25.0 mmol) in ethanol (125 ml) was treated with ammonium formate (7.90 g, 125 mmol) and palladium hydroxide on carbon (2.81 g, 20% b/w palladium). The resulting suspension was purged with nitrogen and then heated to reflux for an hour. The reaction mixture was cooled to room temperature and filtered through arbocel to remove catalyst residues. The filtrate was reduced in vacuo and the residue was partitioned between 0.88 ammonia (100 ml) and dichloromethane (100 ml). The organic phase was separated and the aqueous extracted with more dichloromethane (100 ml). The combined organic extracts were dried (sodium sulphate) and the solvent removed in vacuo to give the title compound as a colourless oil (6.25 g, trace solvent remaining by 1H NMR).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1.O[C@H]1CC(=O)C(CCC[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=O)=C1>>[O:33]1[CH2:34][CH2:28][CH2:29][CH2:30][CH:31]1[O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1
Reactant: COC(=O)CCCCCCC1=CC(O)CC1=O
Reactant: COC(=O)CCCCCCC1=C[C@@H](O)CC1=O
Product: COC(=O)CCCCCCC1=CC(OC2CCCCO2)CC1=O

Procedure:
When an equivalent quantity of methyl 7-(3(RS)-hydroxy-5-oxocyclopent-1-en--yl)heptanoate is substituted for the methyl 7-(3(S)-hydroxy-5-oxocyclopent-1-en-1-yl)-heptanoate and the procedure detailed in Part A substantially repeated, there is obtained methyl 7-(3(RS)-tetrahydropyran-2-yloxy-5-oxocyclopent-1-en-1-yl)heptanoate.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][NH:6][CH3:7].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[C:17]([O:36][CH3:37])=[CH:18][CH:19]=[C:20]2[C:25]=1[O:24][C:23](=[O:26])[CH:22]=[C:21]2[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[CH:30][C:29]=1[Cl:35]>>[Cl:35][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([Cl:34])[C:28]=1[NH:27][C:21]1[C:20]2[C:25](=[C:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:8])[CH3:1])[CH3:7])[C:17]([O:36][CH3:37])=[CH:18][CH:19]=2)[O:24][C:23](=[O:26])[CH:22]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: CNCCCN(C)C
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN(C)CCCN(C)C

Procedure:
The title compound was prepared from N1,N1,N3-trimethylpropane-1,3-diamine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 8.53 (s, 2H), 7.84 (d, 1H), 7.03 (d, 1H), 4.17 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.54 (t, 4H), 2.45 (t, 2H), 2.31 (s, 3H), 2.27 (s, 6H), 1.69 (m, 2H), 1.64 (m, 2H), 1.56 (m, 2H), 1.47 (m, 2H); MS (ESI): 537.1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]1[O:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[N:8]2.[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.O>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]2[O:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[N:8]3)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(CNc2ccc3c(CCl)cccc3n2)o1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CNc2ccc3c(CS(=O)(=O)c4ccc(Cl)cc4)cccc3n2)o1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
(5-Chloromethyl-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (55 mg, 0.192 mmol) were dissolved in 1 mL dimethylformamide and 4-chlorobenzenesulphinic acid sodium salt (47 mg, 0.237 mmol) was added. The reaction mixture was stirred at 60° C. for 3 h. Water was added until a suspension was formed and the mixture was stirred for 15 min. The solid was filtered off and dried. The title compound was obtained as a brown solid (53 mg, 65%), MS: m/e=427.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>>[CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][N:5]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CCNCC1
Product: CCC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Yield: 51.7 %

Procedure:
Following the procedure used in Step H of example 14 and starting from (3aS,7aS)-3-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-one (HCl salt, 1.5 g, 3.8 mmol) and propanoyl chloride (0.43 mL, 4.89 mmol), the title compound (740 mg, 51.7%) was obtained after purification by flash chromatography (4% MeOH in dichloromethane). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.96 (s, 3H), 1.18 (t, 3H), 1.3-1.5 (m, 6H), 1.4-1.9 (m, 8H), 1.92-2.02 (m, 1H), 2.1-2.3 (m, 3H), 2.32-2.4 (m, 2H), 2.84-3.08 (m, 4H), 3.23-3.4 (m, 2H), 3.42-3.5 (m, 1H), 3.82-3.88 (m, 1H), 3.7-3.8 (m, 1H), 4.43 (s, 1H). MS (M+1): 377.16
Reaction SMILES: [CH2:1]([S:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)Cl>[CH2:12]([O:11][P:10]([CH2:9][S:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])(=[O:17])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: CCOP(=O)(CSCc1ccccc1)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOP(=O)(CS(=O)Cc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diethyl (benzylthiomethyl)phosphonate (10 g., 0.036 mole) in 75 ml. of methylene chloride was, with ice-bath cooling, treated with 7.29 g. (0.036 mole) of m-chloroperoxybenzoic acid portionwise. After the addition was complete, the mixture was stirred for 1 hour at ambient temperature, filtered to remove precipitate, and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel by eluting the column with ethyl acetate which gave 5.9 g. of the title compound.
Reaction SMILES: C([O:8][N:9]([C:20](=[O:64])[CH2:21][CH2:22][C:23](=[O:63])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]([O:55]CC1C=CC=CC=1)[C:31](=[O:54])[CH2:32][CH2:33][C:34](=[O:53])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]([O:45]CC1C=CC=CC=1)[C:42](=[O:44])[CH3:43])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]([C:20](=[O:64])[CH2:21][CH2:22][C:23](=[O:63])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]([OH:55])[C:31](=[O:54])[CH2:32][CH2:33][C:34](=[O:53])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]([OH:45])[C:42](=[O:44])[CH3:43])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19]
Reactant: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(C)=O
Agent: [Pd]
Solvent: CO
Product: COCCOCCOCCN(O)C(=O)CCC(=O)NCCCCCN(O)C(=O)CCC(=O)NCCCCCN(O)C(C)=O
Reaction time: 2 h
Yield: 85.9 %

Procedure:
11,22,33-Trihydroxy-12,15,23,26,34-pentaoxo-11,16,22,27,33-pentaaza-2,5,8-trioxapentatriacontane (2) was prepared by dissolving compound (22) (2.6 g, 2.92 mmol) in distilled CH3OH (200 mL) in acid-washed glassware, and 10% Pd-C (1.1 g) was introduced. The mixture was stirred under a hydrogen atmosphere for 2 hours, solids were filtered using analytical grade Celite and the filtrate was concentrated to furnish 1.56 g (86%) of (2) as an amorphous white solid: NMR (D2O) δ 1.17-1.80 (m, 12 H), 2.11 (s, 3 H), 2.33-2.93 (m, 8 H), 3.15 (t, 4 H, J=7), 3.33 (s, 3 H), 3.46-3.84 (m, 16 H). Analysis: (C27H51N5O11) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].B.C1COCC1.CCO.Cl>C1COCC1.CCOCC.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:12])[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C#N)c1ccc(Cl)c(Cl)c1
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CC(CN)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3,4-Dichloro-phenyl)-propionitrile (5.0 g, 25.0 mmol) was dissolved in THF (80 mL). BH3.THF (1 M in THF, 27.5 mL, 27.5 mmol) was added and the mixture was stirred overnight at rt. EtOH (10 mL) was added, the mixture was stirred for 20 min, and HCl in Et2O (2 M, 12.5 mL) was added. After stirring for 1 h, water was added, causing precipitation of the product. The product was collected by suction filtration and dried (4.2 g, 70%). MS (ESI+): mass calcd. for C9H11Cl2N, 204.1; m/z found, 205 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.45-7.42 (m, 2H), 7.17-7.15 (m, 1H), 3.05-3.02 (m, 2H), 2.98-2.96 (m, 1H), 1.24 (d, J=6.5, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1.CC#N.O>CCCCO>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Solvent: CCCCO
Solvent: CC#N
Solvent: O
Product: COc1cccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)c1
Temperature: 155 °C
Yield: 74.1 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxybenzamide (215 mg, 0.590 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (414 mg, 2.07 mmol) were placed in n-BuOH (5 mL) and heated to 155° C. for 72 hours. The reaction was then cooled to room temperature and concentrated to dryness. The crude residue was purified by C-18 reverse phase flash chromatography (Biotage Horizon unit, C-18 25M column, 5-90% CH3CN/water gradient) to give (R)-tert-butyl 1-(5-bromo-3-(3-methoxybenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (238 mg, 74% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4][CH2:5][NH:6][C:7](=[O:34])/[CH:8]=[CH:9]/[C@@H:10]([NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].CNCCN>>[N:3]1([CH2:4][CH2:5][NH:6][C:7](=[O:34])/[CH:8]=[CH:9]/[C@@H:10]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:1][CH2:2][CH2:36][CH2:35]1
Reactant: CCN(CC)CCNC(=O)/C=C/[C@H](Cc1ccccc1)NC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CNCCN
Product: O=C(/C=C/[C@H](Cc1ccccc1)NC(=O)Nc1ccc(-c2ccccc2)cc1)NCCN1CCCC1

Procedure:
Prepared as in Example 18, step B, from (E)-(S)-4-(3-biphenyl-4-yl-ureido)-5-phenyl-pent-2-enoic acid (Example 19, step A), substituting 2-pyrrolidin-1-yl-ethylamine for N′-methyl-ethane-1,2-diamine. MS (electrospray): mass calculated for C30H3N4O2, 482.27; m/z found, 483.3 [M+H]+, 505.2 [M+Na]+, 987.5 [2M+H]+. 1H NMR (400 MHz, CDCl3): 7.99 (s, 1H), 7.53 (d, J=7.4 Hz, 2H), 7.49–7.37 (m, 7H), 7.32–7.20 (m, 5H), 6.80 (dd, J=15.3, 5.1 Hz, 1H), 5.97–5.93 (m, 2H), 4.89–4.83 (m, 1H), 4.51–4.45 (m, 1H), 3.63–3.55 (m, 1H), 3.28–3.21 (m, 1H), 2.95 (dd, J=13.7, 7.3 Hz, 1H), 2.87 (dd, J=13.7, 7.3 Hz, 1H), 2.72–2.65 (m, 2H), 2.53–2.45 (m, 4H), 1.78–1.69 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C@H:7]1[OH:19])=[O:4].[H-].[Na+]>C1COCC1>[O:4]=[C:3]1[CH2:2][O:19][C@@H:7]2[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11][C@H:6]2[NH:5]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)CCl)[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]2NC(=O)CO[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 9.6 %

Procedure:
To a stirred mixture of 249B (410 mg, 14.0 mmol) in 10 mL of dry THF under N2 at room temperature was added 60% NaH (84.0 mg, 2.10 mmol). This mixture was stirred at room temperature for 45 min and quenched with 3 mL of saturated NH4Cl solution. The mixture was concentrated in vacuo and diluted with 40 mL of saturated NaHCO3 solution. The aqueous solution was extracted with EtOAc (3×60 mL). The combined EtOAc extracts were washed with brine (1×30 mL). The EtOAc layer was dried (MgSO4), filtered and concentrated in vacuo to give 344 mg (yield: 96%) of 249C. It had an analytical HPLC retention time=2.01 min. (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm) and a LC/MS M+=257.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][OH:25])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH:24]=[O:25])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
Dimethyl sulfoxide (0.85 ml) was added to a solution of 0.50 ml of oxalyl chloride in 10 ml of dichloromethane at -60° C. and, 3 minutes later, a solution of 1.08 g of 1-tert-butoxycarbonylpiperidine-3-methanol in 10 ml of dichloromethane was added dropwise over 5 minutes. After stirring for 15 minutes, 3.0 ml of triethylamine was added to the reaction mixture. After further 5 minutes of stirring, water (20 ml) was added to the reaction mixture and, after shaking, the dichloromethane layer was separated. The dichloromethane layer was washed with 1N hydrochloric acid, water, saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride in that order, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 0.98 g of 1-tert-butoxycarbonylpiperidine-3-carbaldehyde.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]4[O:9][CH:8]([CH3:10])[CH2:7][C:6]=4[C:11]=3[CH3:12])[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1c(C)c(Br)c(C)c2c1OC(C)C2
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)C4)CC2)c1
Yield: 44.4 %

Procedure:
By using 5-bromo-7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (542 mg, 2.0 mmol) synthesized in Reference example 83 and 1-(3-methoxyphenyl)piperazine (768 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to obtain the title compound 340 mg (yield 44%) as an oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[N:7]([CH2:15][CH:16]([O:19][CH3:20])[O:17][CH3:18])[N:6]=[CH:5]2.[C:21](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.C(OCC)(=O)C>CN(C=O)C.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>[CH3:18][O:17][CH:16]([O:19][CH3:20])[CH2:15][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:21])=[CH:10][C:9]=2[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[N:6]1
Reactant: COC(=O)c1cc(Br)cc2cnn(CC(OC)OC)c12
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)cc2cnn(CC(OC)OC)c12
Temperature: 100 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
To methyl 5-bromo-1-(2,2-dimethoxyethyl)-1H-indazole-7-carboxylate from Step D of Example 10 in DMF (100 mL) was added potassium carbonate (622 mg, 4.5 mmol), tetrakis(triphenylphosphine)palladium(0) (347 mg, 0.3 mmol) and trimethylboroxine (377 mg, 3.0 mmol) and the reaction mixture was stirred at 100° C. for 24 h. Then another portion of trimethylboroxine (377 mg, 3 mmol) was added and the reaction was further stirred for 6 h. Ethyl acetate was added and the reaction was washed with water and concentrated in vacuo. The crude mixture was purified by column chromatography (silica gel, 0-30% ethyl acetate/hexanes) to afford methyl 1-(2,2-dimethoxyethyl)-5-methyl-1H-indazole-7-carboxylate (213 mg, 51%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 4.92 (d, J=5.5 Hz, 2H), 4.54 (t, J=5.5 Hz, 1H), 3.98 (s, 3H), 3.28 (s, 6H), 2.47 (s, 3H); MS (ESI+) m/z 279 (M+H).