Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][C:12]=2[Cl:17])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Nc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ncc(Br)cn2)c(Cl)c1
Yield: 78.9 %

Procedure:
Into a flask, 10.0 g of 5-bromo-2-chloropyrimidine, 7.42 g of 4-amino-2-chlorophenol, 14.26 g of potassium carbonate and 100 ml of dimethylsulfoxide were introduced, and reacted in a nitrogen atmosphere at 120° C. for 2.5 hours under stirring. After the completion of the reaction, the product was poured into water, and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography, whereby 12.26 g of oily 4-(5-bromo-2-pyrimidinyloxy)-3-chloroaniline was obtained.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:3].C1COCC1.C(OC(C)C)(C)C>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:1])[CH3:3]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)O)cc1)CO2
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Yield: 65 %

Procedure:
Using N-(3-(4-(1-hydroxyethyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 175, the title compound was synthesized in the same manner as in Example 32. Yield: 65%. Melting point: 181-182° C. (THF-diisopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([NH:31][CH3:32])=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CNC(=O)CCl
Product: CNC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N-methyl-acetamide gave the title compound.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][C:10]1[C:11]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:12][C:13]([NH2:15])=[N:14][C:9]=1[C:8]#[C:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(-c2ccncc2)cc(C#Cc2ccccc2)n1
Solvent: CC#N
Product: Nc1cc(-c2ccncc2)c(Br)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 6-(2-phenylethynyl)-4-(pyridin-4-yl)pyridin-2-amine G1 (93 mg, 0.34 mmol), N-bromosuccinimide (61 mg, 0.34 mmol) and ACN (11 ml) is stirred in the dark at RT for 20 h. The mixture is concentrated in vacuo and the product purified by NP chromatography. Yield: 90 mg (75%). HPLC-MS: M+H=350/352; tR=1.18 min (METHOD—5).
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[N:19]=3)=[CH:13][C:12]=2[F:41])[CH:7]=[CH:6][N:5]=1)(=O)N.[ClH:42].[NH2:43]C1C=C(OC2C=CC(NC3N=CC=CC=3C(NC3C=CC(F)=CC=3F)=O)=CC=2F)C=CN=1>>[ClH:42].[ClH:42].[ClH:42].[NH2:43][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[N:19]=3)=[CH:13][C:12]=2[F:41])[CH:7]=[CH:6][N:5]=1
Reactant: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Reactant: NC(=O)c1cc(Oc2ccc(Nc3nc(N4CCOCC4)ncc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Agent: Cl
Product: Nc1cc(Oc2ccc(Nc3nc(N4CCOCC4)ncc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Yield: 26 %

Procedure:
4-(4-(2-Carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-2-morpholinopyrimidine-5-carboxamide (55 mg, 0.01 mmol) was converted to the title compound (16 mg, 26%) in a manner similar to the preparation of 2-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide (Step E of Example 3). 1H NMR (DMSO-d6) δ 11.24 (s, 1H), 10.20 (s, 1H), 8.85 (s, 1H), 7.92 (m, 2H), 7.82 (br s, 2H), 7.48-7.35 (m, 4H), 7.08 (m, 1H), 6.65 (dd, 1H, J=7.3, 2.5 Hz), 6.12 (d, 1H, J=2.4 Hz), 3.74 (m, 4H) 3.63 (m, 4H); MS(ESI+) m/z 538 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1)=O)C.[CH3:38][NH2:39]>CO>[CH3:38][NH:39][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:19][CH:20]=3)=[N:10][C:9]=2[N:28]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1)=[O:3]
Reactant: CCOC(=O)c1cn(Cc2ccccc2)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cn(Cc2ccccc2)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
8-Benzyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (7.6 mg, 0.015 mmol) was dissolved in MeOH (1 mL) and methylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column; 32 mL/min 5-100% MeCN/H2O gradient over 15 mm) and lyophilized to provide 1.3 mg of 8-benzyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 9.54 (br s, 1H), 9.25 (s, 1H), 8.70 (s, 1H), 7.23-7.30 (m, 5H), 7.13-7.15 (m, 2H), 6.83 (d, 2H, J=8.9 Hz), 5.35 (s, 2H), 3.13 (br s, 4H), 2.91 (s, 3H), 2.53 (br s, 4H), 2.30 (br s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H29N7O2: 483.24, Found: 484.3 (M+H).
Reaction SMILES: [ClH:1].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[OH:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>>[ClH:1].[OH:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)[CH2:14][CH2:15]2)=[CH:22][CH:21]=1
Reactant: c1ccc2cc(CC3CCNCC3)ccc2c1
Reactant: Oc1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc(OCCN2CCC(Cc3ccc4ccccc4c3)CC2)cc1

Procedure:
The title compound was prepared from 4-((2-naphthyl)methyl)piperidine hydrochloride (150 mg, 573 μmol), 2-(4-hydroxyphenoxy)ethyl bromide (130 mg, 602 μmol) and NaHCO3 (97 mg, 1.17 mmol) as a pale yellow solid (182 mg): mp 221-222° C.; 1H NMR (CD3OD) 1.53-1.72 (m, 2H), 1.87-2.12 (m, 3H), 2.81 (d, J=6.9 Hz, 2H), 2.92-3.18 (m, 2H), 3.43-3.70 (m, 4H), 4.25 (t, J=4.8 Hz, 2H), 6.73 (d, J=9.3 Hz, 2H), 6.85 (d, J=9.3 Hz, 2H), 7.32-7.49 (m, 3H), 7.66 (s, 1H), 7.76-7.85 (m, 3H); Anal. Calcd for C24H28ClNO2 ·0.4H2O: C, 71.15; H, 7.16; N, 3.46. Found: C, 71.17; H. 6.80; N, 3.11.
Reaction SMILES: [C:1]12([C:11]3[C:12]([OH:20])=[CH:13][C:14]([OH:19])=[C:15]([CH:18]=3)[CH:16]=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>>[C:1]12([C:11]3[C:12]([O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:13][C:14]([O:19][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[C:15]([CH:18]=3)[CH:16]=[O:17])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=Cc1cc(C23CC4CC(CC(C4)C2)C3)c(O)cc1O
Reactant: COCCOCCl
Product: COCCOCOc1cc(OCOCCOC)c(C23CC4CC(CC(C4)C2)C3)cc1C=O
Yield: 75.2 %

Procedure:
In a manner analogous to that of Example 17(a), 25 g (91.9 mmol) of 5-(1-adamantyl)-2,4-dihydroxybenzaldehyde were reacted with 26.2 ml (0.23 mol) of 2-methoxyethoxymethyl chloride and 31 g (75%) of the expected compound were recovered in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>CN1C(=O)CCC1>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:17])=[O:16]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A solution of N-(5-bromo-2-nitrophenyl)benzenamine (250 mg, 0.85 mmol) and piperazine (366 mg, 4.26 mmol) in NMP (1 mL) was heated to 110° C. for 16 h. The solution whole cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 10 mL of water, dried (high vacuum, 14 h) to furnish 2-nitro-N-phenyl-5-(piperazin-1-yl)aniline (165 mg, 0.55 mmol), 65% yield. 1H NMR (500 MHz, CDCl3) d (ppm) 9.89 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.45 (m, 2H), 7.34 (d, J=7.0 Hz, 2H), 7.25 (t, J=7.0 Hz, 1H), 6.43 (d, J=2.5 Hz, 1H), 6.35 (dd, 2.5 Hz, 9.75 Hz, 1H), 3.29 (m, 4H), 2.92 (m, 4H).+ESI HRMS (calcd for C16H19N4O2, M+1) 299.1508, found 391.150
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].F[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:15]=[CH:14][C:13]=1[C:24]1[N:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[N:25]=1>>[CH3:49][O:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][N:31]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[C:26]2[N:27]=[C:28]([CH3:30])[N:29]=[C:24]([C:13]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[N:17][C:12]=3[NH:10][C:4]3[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[N:25]=2)=[CH:47][CH:46]=1
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(-c4ccncc4)nc3F)n2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(-c4ccncc4)nc3Nc3cnc(OC)c(F)c3)n2)cc1
Yield: 39.6 %

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 5-fluoro-6-methoxypyridin-3-amine (Anichem) and 4-(6-fluoro-2,4′-bipyridin-5-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine. Purification using an ISCO Combiflash Companion (12 g column and sample loader, 30-100% EtOAc in hexanes over 20 min; the product eluted with 82% EtOAc) afforded the title compound as a brown oil (39.6%). 1H NMR (400 MHz, d6-DMSO) δ 11.86 (s, 1H); 8.91 (d, J=8.2 Hz, 1H); 8.70-8.76 (m, 2H); 8.21 (d, J=2.2 Hz, 1H); 8.09 (dd, J=12.4, 2.2 Hz, 1H); 7.94-7.99 (m, 2H); 7.66 (d, J=8.0 Hz, 1H); 7.26 (dd, J=18.4, 8.6 Hz, 4H); 6.89 (dd, J=18.7, 8.7 Hz, 4H); 4.83 (d, J=9.2 Hz, 4H); 3.95 (s, 3H); 3.74 (s, 3H); 3.70 (s, 3H); 2.59 (s, 3H). m/z (ESI, +ve ion) 645.0 (M+H)+.
Reaction SMILES: [F:1][CH:2]([C:10](=[O:40])[CH2:11][C@H:12]1[C@@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C@@H:14]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C@@H:13]1[CH2:31][CH2:32][CH:33]([OH:39])[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][CH:2]([C:10](=[O:40])[CH2:11][C@H:12]1[C@@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C@@H:14]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C@@H:13]1[CH2:31][CH2:32][C:33](=[O:39])[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCCCC(O)CC[C@@H]1[C@@H](CC(=O)C(F)CCCC(=O)OC)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCCC(=O)CC[C@@H]1[C@@H](CC(=O)C(F)CCCC(=O)OC)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1

Procedure:
To a solution of methyl 5(RS)-fluoro-6-oxo-7-{(1R,2R,3R,5S)-2-[3(RS)-hydroxy-1-octyl]-3,5-bis-tetrahydropyranyloxy-cyclopentyl]-6-oxo-heptanoate (54) (0.30 g) in acetone was added Jones reagent (2.60M, 0.6 ml) and the resultant mixture was stirred at -30° C. for 1.5 hours. The reaction mixture was treated in the conventional manner and the obtained crude product was subjected to silica gel column chromatography to give the title compound (55) as a mixture of diastereomers. Yield: 0.24 g (80%)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:28]=[CH:27][C:8]([CH:9]([OH:26])[C@@H:10]([C:23]([OH:25])=[O:24])[N:11]([CH3:22])[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1.[N+](=[CH2:31])=[N-]>C(OCC)(=O)C.C(OCC)C>[CH3:31][O:24][C:23](=[O:25])[C@H:10]([CH:9]([OH:26])[C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:28][CH:27]=1)[N:11]([CH3:22])[S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: COCOc1ccc(C(O)[C@@H](C(=O)O)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COCOc1ccc(C(O)[C@@H](C(=O)OC)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
To a solution of O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-hydroxytyrosine (20.0 g) in ethyl acetate (100 ml) was added diazomethane in diethyl ether (80 ml). After stirring for 10 minutes, the solvent was removed in vacuo. The residue was put on a silica gel column (MERCK 7734:500 g) and eluted with chloroform to give O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-hydroxytyrosine methyl ester. (threo isomer: 8.82 g, erythro isomer: 6.63 g)
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:3]1.C(N)CN.[N+:17]([CH3:20])([O-:19])=[O:18]>>[CH3:1][CH:2]1[C:7]([CH2:20][N+:17]([O-:19])=[O:18])=[CH:6][CH2:5][N:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:3]1
Reactant: COC(=O)N1CCC(=O)C(C)C1
Reactant: C[N+](=O)[O-]
Solvent: NCCN
Product: COC(=O)N1CC=C(C[N+](=O)[O-])C(C)C1
Yield: 87.2 %

Procedure:
A mixture of 64 parts of methyl 3-methyl-4-oxo-1-piperidinecarboxylate, 305 parts of nitromethane and 3.02 parts of 1,2-ethanediamine was stirred and refluxed for 4 hours. The reaction mixture was evaporated. The residue was taken up in trichloromethane. The solution was washed twice with a dilute hydrochloric acid solution, dried, filtered and evaporated, yielding 70 parts (87.2%) of methyl 3,6-dihydro-3-methyl-4-(nitromethyl)-1(2H)-pyridinecarboxylate as a residue (intermediate 1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH:24]([CH3:26])[CH3:25])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][N:30]([CH3:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1>>[CH3:29][N:30]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH:24]([CH3:25])[CH3:26])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=3[CH:10]=2)=[CH:34][CH:33]=1)[CH3:47]
Reactant: Cc1cc(C(C)C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: Cc1cc(C(C)C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-{[6-methyl-4-(1-methylethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1H-indazole-4-carboxamide (90 mg, 0.202 mmol) and dimethyl{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}amine (90 mg, 0.303 mmol). The product was collected as a white solid (54 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (br. s., 1H) 8.69 (br. s., 1H) 8.37 (s, 1H) 8.10 (s, 1H) 7.86 (s, 1H) 7.82 (s, 1H) 7.80 (s, 1H) 7.42 (s, 1H) 7.40 (s, 1H) 6.02 (s, 1H) 5.17 (dt, J=13.14, 6.57 Hz, 1H) 4.47 (d, J=4.80 Hz, 2H) 3.44 (s, 2H) 3.24 (dt, J=13.71, 6.92 Hz, 1H) 2.17 (s, 6H) 2.15 (s, 3H) 1.51 (s, 3H) 1.49 (s, 3H) 1.11 (s, 3H) 1.09 (s, 3H). LC-MS (ES) m/z=500.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].OO.FC(F)(F)C(O)=[O:15]>ClCCl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:15])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccncc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: OO
Solvent: ClCCl
Product: N#Cc1cc[n+]([O-])cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
9.6 g of 3-chloro-4-cyanopyridine was dissolved in 70 ml of dichloromethane. Then, 23.2 g of a 31% hydrogen peroxide aqueous solution and 16.0 g of trifluoroacetic acid were added thereto, and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction solution was extracted with dichloromethane. The organic layer was washed sequentially with an aqueous sodium hydrogen carbonate solution and an aqueous sodium hydrogen sulfite solution and the dried over anhydrous magnesium sulfate. Then, dichloromethane was distilled off under reduced pressure. The obtained residue was washed with isopropyl ether to obtain 7.2 g of 3-chloro-4-cyanopyridine N-oxide as a white powder (melting point: 172° to 174° C.). Then, 20 ml of phosphorus oxychloride was added to this 3-chloro-4-cyanopyridine N-oxide, and the mixture was refluxed under heating for 5 hours. After cooling, the reaction solution was gradually poured into an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 3.2 g of 4-cyano-2,5-dichloropyridine (melting point: 55° to 58° C.) and 2.5 g of 4-cyano-2,3-dichloropyridine (melting point: 65° to 69° C.).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[C:11][CH3:12])[CH2:8][CH2:7][C@H:6]1[C:13]#[N:14])=[O:4].[NH2:15][C:16]1([CH2:21][OH:22])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[OH:22][CH2:21][C:16]1([NH:15][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]#[C:11][CH3:12])[CH2:8][CH2:7][C@H:6]2[C:13]#[N:14])=[O:4])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: NC1(CO)CCCC1
Solvent: CC#N
Product: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1(CO)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.03 g, 0.14 mmol, Example 88D) in acetonitrile (1 mL) at room temperature was added 1-amino-1-cyclopentanemethanol (35 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/97% dichloromethane to provide the titled compound. MS (ESI) m/z 290 (M+H)+; 1H NMR (DMSO) δ ppm 4.86 (m, 1H), 4.16 (m, 1H), 3.52 (m, 2H), 3.44 (m, 2H), 2.06-2.39 (m, 4H), 1.96 (m, 2H), 1.86 (d, 3H), 1.75 (m, 6H), 1.56 (m, 2H).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]1[O:24][C:23]2[C:16](=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=[O:19])[O:15]1>CC(C)=O>[CH2:14]1[O:24][C:23]2[C:16](=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]([OH:3])=[O:19])[O:15]1
Reactant: CC(C)=O
Reactant: O=Cc1cccc2c1OCO2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cccc2c1OCO2
Reaction time: 4 h
Yield: 1805.8 %

Procedure:
Freshly prepared Jones reagent (0.2 mmol) was added dropwise (until a brown color persisted in the reaction) to a solution of 2-methylenedioxybenzaldehyde (1.0 g, 6.67 mmol) in 10 mL of acetone at 0° C. The reaction was completed after 4 hours at 0° C., and it was poured onto ethyl ether (20 mL). The ether solution was then washed with brine and extracted with 1N NaOH solution. The NaOH extract was acidified with concentration HCl, and product was extracted out with ether (3×10 mL). Ether layers were combined, dried, and evaporated to give 0.6 g pure product; this compound was used for the next step without further purification (54%). M+167.0
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([O:7][C:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of cyclopentanecarboxylic acid (1.14 g, 10 mmol) in DMF (15 mL) is added K2CO3 (2.07 g, 15 mmol) and benzyl bromide (1.71 g, 10 mmol). The suspension is stirred at room temperature for 18 hours. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane:EtOAc, 10:1) to give cyclopentanecarboxylic acid benzyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]([O:19]C)=[O:18])=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>C1COCC1.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]([OH:19])=[O:18])=[N:9]2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1nn(Cc2ccc(OC)cc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C(=O)O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.7 %

Procedure:
Methyl 1-(4-methoxybenzyl)-3-indazolylcarboxylate (830 mg, 2.80 mmol) was dissolved in THF (22 ml). To the resulting solution was added 0.25N NaOH (22 ml, 5.60 mmol). The resulting mixture was stirred for 15 hours at room temperature. The reaction mixture was poured in 1N HCl (50 ml), followed by extraction with chloroform (2×100 ml). The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was dissolved in chloroform and hexane was added to the resulting solution until precipitation appeared. The crystals thus precipitated were collected by filtration under reduced pressure and dried for 12 hours under reduced pressure to give 1-(4-methoxybenzyl)-3-indazolylcarboxylicacid (630 mg, 80%) as a colorless amorphous substance.