Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=3)=[O:15])[C:6]=2[CH:35]=1.N1C=CC=CC=1.[CH3:42][S:43]Cl>O>[CH2:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:43][CH3:42])=[CH:35][C:6]=2[C:7]=1[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:20][CH:21]=1)=[O:15])[CH2:11][CH2:12][CH3:13]
Reactant: CSCl
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCc1oc2ccc(NSC)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
4.78 g of (5-amino-2-butyl-benzofuran-3-yl)-[4-(3-dibutylamino-propoxy)-phenyl]-methanone (III) (0.01 mol, 1 eq) and 35 mL of pyridine were placed into a flask. The mixture was cooled down to 0° C. and 0.99 g of methanesulfenyl chloride (II) (0.012 mol, 1.2 eq; freshly prepared as described in the above mentioned literature) was added in 10 min. The mixture was stirred at 0° C. for 3 hours and then heated to room temperature and stirred for 6 hours. The mixture was poured into 100 mL of water. The product was extracted with 50 mL of dichloromethane. The organic phase was washed with 30 mL of water. The solvent was evaporated and the product was purified by column chromatography (column: spheric silica (60 Å); eluent: toluene:ethyl acetate=70:30) to obtain 2.2 g of compound (IV) (42%) as a light yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]([OH:24])=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Cl)=[CH:42][CH:41]=1>CN(C=O)C.CCOCC>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][N:12]([CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:22]([O:24][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([O:39][CH3:38])=[CH:41][CH:42]=2)=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(C(C(=O)O)c2ccccc2Cl)C[C@@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C(c2ccccc2Cl)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of crude 2-(R/S)-(3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidin-1-yl)-(2-chlorophenyl)acetic acid (from EXAMPLE 10, Step A), 338 mg (1.0 mmol) of cesium carbonate and 0.14 mL (1.0 mmol) of 4-(methoxy)benzyl chloride in 3 mL of DMF was stirred at rt for 22 h. The reaction mixture was diluted with 100 mL of ether and washed with 100 mL of 1.0 N NaHCO3. The layers were separated and the aqueous phase was extracted with 100 mL of ether. The combined organic phases were dried over MgSO4 and concentrated. Flash chromatography using 9:1 v/v hexanes/EtOAc as the eluant afforded 377 mg (63%, two steps) of the title compound: RF: 0.68 (4:1 v/v hexanes/EtOAc). For the pair of diastereomers: 1H NMR (300 MHz) δ 0.0, 0.01, 0.02,0.04 (4s, 6H), 0.86,0.88 (2s, 9H), 2.42 (m, 1H), 2.67 (m, 1H), 2.84-3.10 (m, 4H), 3.57-3.62 (m, 2H), 3.83 (s, 31), 4.80, 4.81 (2s, 1H), 5.10 (ABq, J=12.1, 2H), 6.83-6.87 (m, 2H), 7.20-7.41 (m, 10H), 7.73 (m, 1H).
Reaction SMILES: [Li][CH2:2]CCC.[Si:6]([O:13][CH:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CI>C1COCC1>[Si:6]([O:13][CH:14]1[CH2:15][CH2:16][C:17]([CH3:2])([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8]
Reactant: COC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of anhydrous DIPA (26.7 g, 263.86 mmol, 3.00 equiv) in freshly distilled THF (500 mL) was added n-BuLi (2.5 M in hexane, 110 mL) dropwise with stirring at −78° C. under nitrogen. After the addition, the resulting solution was stirred for 0.5 h at −78° C. To this was added dropwise a solution of methyl 4-[(tert-butyldimethylsilyl)oxy]cyclohexane-1-carboxylate (24 g, 88.09 mmol, 1.00 equiv) in 50 mL of THF and the resulting solution was allowed to react for an additional 1 h at −78° C. To the mixture was added CH3I (62.64 g, 441.31 mmol, 5.01 equiv) dropwise with stirring at this low temperature. Stirring was continued for 1 h. The reaction was quenched with water and extracted with 3×150 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10) to provide the desired methyl 4-[(tert-butyldimethylsilyl)oxy]-1-methylcyclohexane-1-carboxylate (22.0 g, 87%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:16]([CH3:17])=[C:15]([Cl:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[OH:11])=[O:5].C1C=CC=CC=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[Cl:1][C:2]1[C:16]([CH3:17])=[C:15]([Cl:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[O:11][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: Cc1c(Cl)ccc(C(=O)c2cnn(C)c2O)c1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1c(Cl)ccc(C(=O)c2cnn(C)c2OCc2ccccc2)c1Cl
Reaction time: 2 h
Yield: 89 %

Procedure:
1.43 g (0.005 mol) of 4-(2,4-dichloro-3-methylbenzoyl)-1-methyl-5-hydroxypyrazole was dissolved in 20 ml of benzene containing 0.50 g (0.005 mol) of triethylamine, and 0.86 g (0.005 mol) of benzylbromide was added thereto. Then, the reaction mixture was refluxed with stirring for 2 hours. After cooling, the precipitated salt was filtered off, and benzene was distilled off from the residual solution under reduced pressure. The resulting oily product was purified through a silica gel column chromatography (eluent:benzene) to obtain 1.67 g of the title compound (yield 89%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:20]2[CH2:22][CH2:21]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:42])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]C(=O)C)=[CH:33][C:32]=1[CH3:41])([CH3:29])[CH3:28])[CH3:24].CO.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:23]([O:25][C:26](=[O:42])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:2][C:3]2[C:4]([CH:20]3[CH2:22][CH2:21]3)=[N:5][C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[N:7][CH:8]=2)=[CH:33][C:32]=1[CH3:41])([CH3:28])[CH3:29])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(C)=O)cc1C
Reactant: FC(F)(F)Oc1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(SCc2cnc(-c3ccc(OC(F)(F)F)cc3)nc2C2CC2)cc1C
Temperature: 25 °C
Reaction time: 27 h
Yield: 78.3 %

Procedure:
0.399 g (1.2 mmol) of 5-Chloromethyl-4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine (example 150D]) and 0.300 g (1.0 mmol) of 2-(4-acetylsulfanyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 142C]) were dissolved in 2.0 ml of acetonitrile and 0.08 ml of MeOH and treated with 0.462 g (1.4 mmol) of Cs2CO3. After vigorous stirring for 27 h at ambient temperature and filtration, the solvent was evaporated and the residue redissolved in dichloromethane and filtered again and evaporated. Purification by flash chromatography (SiO2, dichloromethane/n-heptane 1:2 to 4:1 and then AcOEt) afforded 0.428 g of the title compound as colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:9][C:10]([O:31][CH3:32])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[C:17]([C:29]#[N:30])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:29]([C:17]1[C:18]([C:20]2[CH:21]=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:31][CH3:32])=[CH:9][C:8]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:30]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C#N)c(-c2cnn3ccccc23)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Yield: 69.2 %

Procedure:
A solution of acryloyl chloride (0.017 mL, 0.21 mmol) in CH2Cl2 (0.6 mL) was added to a mixture of 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile (Intermediate 65, 87 mg, 0.19 mmol) and DIPEA (0.063 mL, 0.38 mmol) in CH2Cl2 (1.5 mL) at 0° C. The mixture was then stirred at 0° C. for 4 h. (during this time a further 0.5 eq acryloyl chloride was added). The mixture was then diluted with CH2Cl2, washed twice with sat. NaHCO3, then with water, and then dried (MgSO4). Purification by FCC, eluting with 0-6% methanolic ammonia in CH2Cl2 gave the title compound (67 mg, 69%) as a yellow solid; 1H NMR: (102° C.) 2.30 (3H, s), 2.56-2.59 (4H, m), 2.93-2.96 (4H, m), 3.78 (3H, s), 5.67-5.7 (1H, m), 6.16 (1H, d), 6.44-6.51 (1H, m), 6.95 (1H, s), 7.11 (1H, t), 7.35 (1H, t), 8.20 (1H, s), 8.32 (1H, d), 8.66 (1H, s), 8.72 (1H, br s), 8.76 (1H, d), 8.91 (1H, s), 8.96 (1H, br s); m/z: ES+ MH+ 510.5.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:41][CH3:42])[C:25]([F:43])=[CH:24][N:23]=1>>[F:43][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[CH:31][C:30]=2[O:41][CH3:42])=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1F
Product: COc1cc2c(cc1Nc1ncc(F)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.037 g, 39%). MP: 80-107° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.30 (d, 1H, J=8.6 Hz), 8.13 (s, 1H), 7.93-7.90 (m, 1H), 7.39 (s, 1H), 7.22-7.18 (m, 1H), 6.63 (s, 1H), 6.56-6.49 (m, 2H), 3.93-3.88 (m, 7H), 3.86 (s, 3H), 3.27 (s, 2H), 3.17-3.12 (m, 7H), 2.98 (s, 3H), 2.91-2.85 (m, 4H), 2.74-2.65 (m, 4H). MS: 580.32 (MH)+.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])/[CH:13]=[CH:14]/[C:15](OC)=[O:16])=[C:7]([C:20](=[O:27])[NH:21][CH:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:13]2[CH2:14][C:15](=[O:16])[NH:3][NH:2]2)=[O:19])=[C:7]([C:20](=[O:27])[NH:21][CH:22]([CH:24]2[CH2:26][CH2:25]2)[CH3:23])[CH:6]=1
Reactant: NN
Reactant: COC(=O)/C=C/C(=O)Nc1ccc(Cl)cc1C(=O)NC(C)C1CC1
Solvent: O
Solvent: CCO
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(=O)NN1)C1CC1
Yield: 28.6 %

Procedure:
A mixed liquid of 90 mg of hydrazine monohydrate and 3 ml of ethanol, was added to a mixed liquid of 0.56 g of methyl 4-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylamino)-4-oxocrotonate and 3 ml of ethanol, followed by rinsing with 2 ml of ethanol and then by heating and refluxing for 6 hours. The reaction liquid was left to cool, and then, the precipitated crystals were collected by suction filtration, and the crystals were washed with ethanol and air-dried to obtain 0.16 g of the desired product (melting point: 248° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:17]([OH:21])[C:18]([CH3:20])=[CH2:19])=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(C)C(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H](O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1

Procedure:
This compound was prepared from ketone 67 (0.70 g, 1.85 mmol) in a synthetic procedure similar to that for compound and obtained after column chromatography (10%->25% EtOAc/PE) as a colorless oil (yield: 0.71 g, 1.85 mmol, quant.). 1H NMR (400 MHz, CDCl3): δ=7.32-7.18 (m, 7H), 7.04 (d, J=8.15 Hz, 2H), 6.77 (s, 1H), 5.17 (d, J=9.01 Hz, 1H), 5.05-4.91 (m, 4H), 4.14-4.10 (m, 1H), 4.05-3.97 (m, 1H), 3.01 (s, 1H), 2.86-2.78 (m, 1H), 2.64 (dd, J=14.18, 9.64 Hz, 1H), 1.76 (s, 3H), 1.50 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3): δ=156.03, 152.82, 144.45, 136.48, 136.33, 132.60, 129.65, 128.24, 127.79, 127.70, 118.49, 112.28, 80.17, 76.61, 66.37, 54.06, 33.46, 28.20, 18.71 ppm. [α]D23=−13.8 (c=1, CHCl3). HRMS: calcd. for C25H32N2O5 441.23840 [M+H]+. found 441.23843.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[C:10]([CH2:11]O)=[CH:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:6]=1.S(Cl)([Cl:25])=O>ClCCl.CCOCC>[Cl:25][CH2:11][C:10]1[C:5]([CH2:4][CH2:3][O:2][CH3:1])=[N:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:8][CH:9]=1
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Yield: 100 %

Procedure:
A solution of 3.23 g (10.34 mmol) [4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol and 0.788 ml (10.86 mmol) thionylchloride in 30 ml dichloromethane was stirred for 1 h at RT. The reaction mixture was taken up in ether and washed with sodium bicarbonate solution and water. The ether phase was concentrated under reduced pressure to give 3.42 g of pure 5-chloromethyl-4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:12]([CH3:15])([CH3:14])[CH3:13])[S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[Si:16]([O:23][CH2:24][C:25]1[C:30]([B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:40])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:12]([C:5]1[S:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:3]([CH2:2][NH:40][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([B:31]3[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:38])([CH3:39])[O:32]3)[C:25]=2[CH2:24][O:23][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[N:4]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC1(C)OB(c2cccc(N)c2CO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: COC(=O)c1sc(C(C)(C)C)nc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1sc(C(C)(C)C)nc1CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1CO[Si](C)(C)C(C)(C)C
Temperature: 45 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
A suspension of 125a (1 g, 3.4 mmol), 2-((tert-butyldimethylsilyloxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (125b) (1.1 g, 3.1 mmol) and cesium carbonate (1.3 g, 4.1 mmol) in acetonitrile (30 mL) was stirred at 45° C. overnight. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure. The residue was purified on silica gel eluting with 0 to 1% EtOAc in petroleum ether to afford 125c as yellow oil (1.1 g, 56%). LCMS: (M+H)+ 575.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS[C:20]1[NH:21][CH:22]=[C:23]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[N:32][CH:33]=2)[C:24](=[O:26])[N:25]=1.C(O)(=O)C(C(C(O)=O)O)O>N1C=CC=CC=1.C(O)(C)C>[N:1]1([CH2:7][C:8]2[CH:9]=[N:10][N:11]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:20]3[NH:21][CH:22]=[C:23]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[N:32][CH:33]=4)[C:24](=[O:26])[N:25]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1nc(=O)c(Cc2ccc(C)nc2)c[nH]1
Reactant: NCCCOn1cc(CN2CCCCC2)cn1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Cc1ccc(Cc2c[nH]c(NCCCOn3cc(CN4CCCCC4)cn3)nc2=O)cn1

Procedure:
3.5 g of 3-(4-piperidinomethylpyrazol-1-yloxy)propylamine and 3.6 g of 2-methylthio-5-(2-methylpyrid-5-ylmethyl)-1H-pyrimid-4-one in 30 ml of pyridine are refluxed for 30 hours. The pyridine is distilled off and the residue is then chromatographed over neutral Al2O3 (activity level III) using methylene chloride/3% strength methanol as the mobile phase. The oil obtained is reacted with tartaric acid in isopropanol to give an amorphous solid.
Reaction SMILES: C(CC(O)=O)C.[C:7]([N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:15]([C:22](O)=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C[N:33]1CCOCC1.ClC(OCC(C)C)=O.C(OC[C@@H](N)CC(C)C)C>C(OCC)(=O)C>[C:7]([N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[C@H:15]([C:22]([NH2:33])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCOC[C@@H](N)CC(C)C
Solvent: CCCC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](Cc1c[nH]cn1)C(N)=O
Reaction time: 0.25 h

Procedure:
A mixture of Nα -Nim -bis-BOC-histidine ethyl acetate solvale (1.92 g, 5.0 mmol), 4-methylmorpholine (0.55 mL, 5.0 mmol) and isobutyl chloroformate (0.65 mL, 5.0 mmol) in ethyl acetate (50 mL) was stirred in an ice bath under N2 for 15 minutes. A solution of (S)-1-ethoxy-2-amino-4-methylpentane (0.73 g, 5.0 mmol) in ethyl acetate (2 mL) was then added and the reaction stirred at room temperature for 20 hours. After washing with 10% citric acid, brine, saturated NaHCO3 solution and brine, the ethyl acetate extract was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was flash chromatographed over silica gel. Elution with a mixture of 2% methanol and 98% chloroform afforded pure BOC-protected histidineamide (0.90 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][CH:13](O)[CH3:14].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH:13]([CH3:14])[CH3:12])=[O:10]
Reactant: O=C(O)Cc1ccccc1I
Reactant: CC(C)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)Cc1ccccc1I
Temperature: 25 °C

Procedure:
A solution of 2-(2-iodophenyl)acetic acid (0.50 g) and propan-2-ol (0.142 ml) in dry dimethylformamide (10 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.458 g) with stirring at ambient temperature under an atmosphere of argon. After 18 hours the reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (3×50 ml) and brine. The aqueous layers were back-extracted with ethyl acetate (50 ml) and the organic layers were combined, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel (Varian Band Elut S1 silica gel) eluting with dichloromethane to give 2-propyl 2-(2-iodophenyl)acetate (232 mg) as a yellow oil, NMR: 1.2(6H, d), 3.8(2H, s), 4.9(1H, m), 7.0(1H, m), 7.4(2H, d) and 7.85(1H, d).
Reaction SMILES: BrC(C(OCC)=O)C(OCC)=O.C(N(CC)CC)C.[CH3:20][C:21]([CH3:33])([CH2:31][SH:32])[C:22]([NH:24][C@H:25]([C:28]([OH:30])=[O:29])[CH2:26][SH:27])=[O:23].Cl>C(Cl)Cl>[CH3:20][C:21]1([CH3:33])[CH2:31][S:32][S:27][CH2:26][C@@H:25]([C:28]([OH:30])=[O:29])[NH:24][C:22]1=[O:23]
Reactant: CC(C)(CS)C(=O)N[C@@H](CS)C(=O)O
Agent: CCOC(=O)C(Br)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CSSC[C@@H](C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of diethyl bromomalonate (10.5 g) and triethylamine (8.5 g) in methylene chloride (3.8 l), N-(2,2-dimethyl-3-mercaptopropionyl)-L-cysteine (9.5 g) dissolved in methylene chloride (0.3 l) was added dropwise under ice-salt cooling. After the addition, the reaction mixture was stirred for 30 minutes at the same temperature and for 30 minutes at room temperature. The mixture was acidified with 6N hydrochloric acid and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Separated crystals were collected by filtration to give 6.1 g (65%) of the titled compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]([CH2:13][C:14]([CH3:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:4]1.I([O-])(=O)(=O)=[O:24].[Na+]>[Ru](Cl)(Cl)Cl>[CH3:12][O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([C:2]([OH:24])=[O:1])[CH2:4][CH:5]1[CH2:13][C:14]([CH3:22])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])=[O:10]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)N1CCC(CO)CC1CC(C)(C)c1ccccc1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Product: COC(=O)N1CCC(C(=O)O)CC1CC(C)(C)c1ccccc1
Yield: 86.5 %

Procedure:
The compound was prepared as described in Reference Compound 4, Step 5 starting from methyl 4-(hydroxymethyl)-2-(2-methyl-2-phenylpropyl)piperidine-1-carboxylate (8.0 g, 26.2 mmol), sodium periodate (16.8 g, 78.6 mmol) and ruthenium(III) chloride (0.12 g, 0.58 mmol), which resulted in the title compound (7.24 g, 87%). MS m/z 318 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([Cl:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([Cl:14])=[CH:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(Cl)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)n1cc(Cl)c2c(C(=O)O)cc(Br)cc21
Temperature: 55 °C
Yield: 56 %

Procedure:
To a solution of methyl 6-bromo-3-chloro-1-(1-methylethyl)-1H-indole-4-carboxylate (1.2 g, 3.63 mmol) in THF (2.368 ml) and MeOH (14.21 ml) was added 3N NaOH (1.573 ml, 4.72 mmol). The resulting mixture was heated at 55° C. for 4 h. The reaction was removed from the heat and the solvent removed in-vacuo. The remaining residue was dissolved with water (12 ml) and made acidic dropwise with 1N HCl. The product precipitated and the slurry became too thick to stir and was diluted with water (10 ml). After the precipitation halted no more acid was added. The solid was collected by vacuum filtration, washed with water, and air dried under vacuum overnight to give 6-bromo-3-chloro-1-(1-methylethyl)-1H-indole-4-carboxylic acid (650 mg, 2.033 mmol, 56.0% yield over 2 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 8.09 (d, J=1.77 Hz, 1H), 7.89 (s, 1H), 7.45 (d, J=1.77 Hz, 1H), 4.88 (quin, J=6.63 Hz, 1H), 1.43 (d, J=6.57 Hz, 6H). MS(ES) [M+H]+ 316.0.