Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])=[O:4].[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14][Br:25])=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])=[O:4]
Reactant: COC(=O)c1cc2cc(C)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2cc(CBr)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 114.2 %

Procedure:
1-BOC-5-methyl-7-nitro-indole-2-carboxylic acid methyl ester (34 g, 101.7 mmol) prepared in Step A was dissolved in carbon tetrachloride (100 mL). N-bromosuccinimide (27.2 g, 152.6 mmol) and AIBN (1.7 g, 10.2 mmol) were added thereto, and the mixture was stirred for 5 h at 80° C. After completion of the reaction, the reaction mixture was distilled under reduced pressure, and purified by column chromatography to give the title compound (48.0 g, Yield 100%).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:11]I>C1COCC1>[CH3:11][N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8]
Reactant: O=C1CCCCCN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCCCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of ε-caprolactam (2.0 g, 17.6 mmol) in anhydrous THF (15 mL) at 0° C. was added NaH, 60% dispersion in oil (1.06 g, 26.0 mmol), and the mixture was stirred at 0° C. for 30 minutes. The cold bath was removed and the mixture was stirred at room temperature for 1 hour and then cooled again to 0° C. Methyl iodide (1.65 mL, 26.0 mmol) was added dropwise over 10 minutes, then the cold bath was removed and the mixture was stirred at room temperature for 18 hours. The excess NaH was quenched with methanol, THF was removed in vacuo and the crude was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate (2×30 mL), adding solid NaCl to break the emulsion. Organic washings were combined and dried over Na2SO4. Ethyl acetate was removed in vacuo and the crude product 206 (1.54 g, 68%) was used without further purification. MS (ESI)=128 (MH+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:11])=[C:7]([NH:9][NH2:10])[CH:8]=1.C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C>CO>[NH2:20][C:19]1[N:9]([C:7]2[CH:8]=[C:3]([Br:2])[CH:4]=[CH:5][C:6]=2[CH3:11])[N:10]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1ccc(Br)cc1NN
Agent: Cl
Solvent: CO
Product: Cc1ccc(Br)cc1-n1ncc(C#N)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
5 (5-Bromo-2-methylphenyl)hydrazine hydrochloride (CAS no. 214915-80-7) (5 g, 21.05 mmol) was partitioned between EtOAc (50 mL) and NaOH (2M, aq) (30 mL). The organic layer separated and washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated to afford free base of the starting material. The resultant oil was suspended in MeOH (50 mL) under nitrogen at −5° C. 2-(ethoxymethylene)malononitrile (2.57 g, 21.05 mmol) added portionwise over 5 mins and the mixture stirred at ˜0° C. for 30 mins. The reaction mixture was allowed to warm to room temperature and then heated at reflux under nitrogen for 2 hours. The reaction mixture was allowed to cool and evaporated to dryness to afford the product (5.48 g, 94%). 1H NMR (400 MHz, DMSO) 1.99 (3H, s), 6.59 (2H, s), 7.36 (1H, d), 7.49 (1H, d), 7.60-7.63 (1H, m), 7.76 (1H, s); m/z (ES+) (M+H)+=277+279; HPLC tR=2.01 min.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[CH2:27]([N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])[CH2:28][C:29]#[CH:30].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[O:41]=[C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39](=[O:40])[N:31]1[CH2:27][CH2:28][C:29]#[C:30][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C#CCCN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 150 °C
Yield: 76.9 %

Procedure:
Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl ester (0.59 g), 2-(but-3-ynyl)isoindol-1,3-dione (0.3 g), dichlorobis(triphenyl phosphine)palladium (II)(53 mg), copper(I) iodide (29 mg), and triethylamine (0.39 ml) were added to DMF (4 ml). The mixture was heated at 150° C. (microwave reactor) for 10 minutes. The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40→30:70). The purified product was condensed under reduced pressure to give the title compound (0.51 g) as a yellowish-white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.C(Br)(Br)(Br)[Br:26].[CH2:30]([NH:42][C:43](=[O:63])[C:44]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)[C:47]([O:58][CH2:59][CH2:60]O)=[C:46]([Br:62])[CH:45]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CCOC(C)=O>[CH2:30]([NH:42][C:43](=[O:63])[C:44]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)[C:47]([O:58][CH2:59][CH2:60][Br:26])=[C:46]([Br:62])[CH:45]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2cccc(OC)c2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(OC)c2)c1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a flamed dried flask was added triphenylphosphine (98 mg, 0.373 mmol) and 1.5 mL anhydrous THF. This was stirred until all the triphenylphosphine had dissolved. Then CBr4 (123 mg, 0.373 mmol) was added. The reaction mixture was stirred for one-half hour at room temperature then it was cooled to ° C. before N-dodecyl-3-bromo-4-(2-hydroxyethoxy)-5-(3-methoxyphenyl)benzamide (200 mg, 0.373 mmol) was added. The cooling bath was removed after the addition was complete. After the reaction mixture had warmed up to room temperature, 0.2 eq each of triphenylphosphine (19.6 mg, 0.075 mmol) and CBr4 (24.8 mg, 0.075 mmol) were added. The reaction was stirred for one-half hour then the solvent was removed under vacuum to give a yellow semisolid. This material was subjected to flash chromatography (25% EtOAc:75% Hexanes) to yield 150 mg, 67% of a yellow oil. 1H NMR (CDCl3) δ 1.25 (t, J=8.13 Hz, 3H); 1.22-1.40 (m, 18H); 1.52-1.63 (m, 2H); 3.35 (t, J=8.18 Hz, 2H); 3.40 (q, J=6.54 Hz, 2H); 3.84-3.90 (m, 5H); 6.00 (m, 1H); 6.93 (dd, J=8.18 Hz, 2.45 Hz, 1H); 7.07-7.11 (m, 2H); 7.35 (t, J=8.18 Hz, 1H); 7.65 (d, J=2.45 Hz, 1H); 7.39 (d, J=2.45 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=2N)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][C:35]=2[NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cc([N+](=O)[O-])ccc3Sc3ccc(OCc4ccccc4)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.4 %

Procedure:
A solution of the product from Example 10B (62 mg, 0.331 mmol), and the product of Example 63B (120 mg, 0.331 mmol) in acetic acid (1 mL) was stirred in an oil bath preheated to 130° C. for 20 minutes. The mixture was then cooled to room temperature, the acetic acid removed under vacuum leaving a brown oil as the title compound (0.15 g, 92%). The compound was used without purification in the next step.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[N:39]1[CH:44]=[CH:43][C:42]([SH:45])=[CH:41][CH:40]=1>[Cu]I>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([S:45][C:42]5[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=5)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Sc1ccncc1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: CN(C)C=O
Product: c1cc(Sc2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)ccn1
Temperature: 135 °C

Procedure:
Into a sealed tube, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine (0.174 g, 0.465 mmol), Sodium tert-butoxide (134 mg, 1.40 mmol), Copper(I) iodide (8.8 mg, 0.046 mmol), 1,2-Ethanediol (52.1 uL, 0.934 mmol), N,N-Dimethylformamide (6.5 mL, 84 mmol), and Pyridine-4-thiol (0.207 g, 1.86 mmol) were added. The reaction was heated at 135° C. for 2 days. The solvent was removed under vacuum. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give a yellow solid. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN as eluant (5 to 35% ACN). The collected fractions were lyophilized to give a yellow solid. (33 mg, 14%). LCMS (E/I+) 405.7 (M+H). NMR 1H (DMSO-d6)-9.25 (s, 1H), 9.10 (s, 1H), 8.56 (bs, 1H), 7.40 (d, 2H, J=6.68 Hz), 7.33 (d, 2H, J=8.91 Hz), 7.19 (d, 1H, J=4.45 Hz), 7.04 (d, 1H, J=4.45 Hz), 6.70 (d, 2H, J=9.65 Hz), 3.74 (t, 4H, J=5.08 Hz), 302 (t, 4H, J=5.08 Hz).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([OH:20])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=C(S(O[CH2:34][C@:35]2([CH3:38])[CH2:37][O:36]2)(=O)=O)C=CC=1)([O-])=O>CN1CCCC1=O>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([O:20][CH2:34][C@:35]2([CH3:38])[CH2:37][O:36]2)[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(OC(=O)c2ccccc2)cc1O
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(OC(=O)c2ccccc2)cc1OC[C@]1(C)CO1
Yield: 39 %

Procedure:
This compound was prepared from 4-(acetylamino)-3-hydroxyphenyl benzoate (2.71 g, 10 mmol) and [(2S)-2-methyloxiran-2-yl]methyl 3-nitrobenzenesulfonate using the standard procedure and 1-methylpyrrolidin-2-one as a solvent. Flash chromatography on silica gel (ethyl acetate/n-heptane) afforded the subtitled compound as a colourless solid (1.31 g, 3.9 mmol, 39%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Pd].C(O)(C)C>[CH3:1][C:2]1([CH3:10])[CH2:9][CH2:7][CH2:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CC1(C)CCCC(=O)C1
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
312 mg of 5% Pd/C were placed in a 37 mL glass-liner. 4.38 g of dimedone (31 mmol), 7.8 g of isopropanol (10 mL) and 174 mg of p-toluene sulfonic acid (1 mmol) were added. The glass-liner was closed and stirring was started with 500 rpm. The autoclave was flushed three times with 5 bara N2. The stirrer was turned off. The autoclave was pressurized with 5 bara H2 for 10 minutes for pressure check. The pressure was released. The stirrer was turned on again to 500 rpm and the autoclave was heated to 85° C. internal temperature. The autoclave was pressurized with 2 bara H2 and the stirrer was set to 1000 rpm. The reaction mixture was stirred under 2 bara H2 at 85° C. for 2 hours and 50 minutes. Then stirring was slowed to 500 rpm, the autoclave was cooled to a temperature below 25° C. and depressurized. After three times flushing with N2 at 5 bara for 100 minutes stirring was stopped and the autoclave was opened. The content was sucked and filtrated over a 0.45 μm filter. A 30 mL filtrated sample was diluted with 1 mL of isopropanol and 5 mg of NaHCO3 and then analyzed by GC. The total yield of 3,3-dimethylcyclohexan-1-one was 97% with a selectivity of 97%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:25]>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13](=[O:14])[NH2:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCCC1(COCc1ccccc1)C(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1(COCc1ccccc1)C(N)=O

Procedure:
This material was prepared in analogy to example 1 and 2, step A, using 2-benzyloxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.426 g, see example 12, step A) and ammonia solution (320 μL of a 25% solution in water) to give the desired (rac)-2-benzyloxymethyl-2-carbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, MS (ES+): 335.3 (MH+)) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[S:18][C:17]([N:19]([CH3:30])[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)=[N:16][N:15]=1.CC(O)=[O:33].CC(OC(C)=O)=O>CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:3]([C:14]2[S:18][C:17]([N:19]([CH3:30])[CH:20]3[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:26])([CH3:27])[CH2:25]3)=[N:16][N:15]=2)=[C:4]([OH:33])[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1
Reactant: CN(c1nnc(-c2ccc(-c3cnn(C)c3)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CN(c1nnc(-c2c(O)cc(-c3cnn(C)c3)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Example 25) (125 mg, 0.281 mmol) in 1:1 AcOH:Ac2O (2.8 mL) was added Phl(OAc)2 (127 mg, 0.393 mmol) followed by Pd(OAc)2 (6 mg, 0.028 mmol). The reaction mixture was warmed to 80° C. and stirred for 48 hours. The reaction mixture was cooled to room temperature, then diluted with MeOH (10 mL) and loaded onto a 2 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the crude product as a brown glass-like solid. The crude material was taken up in MeOH (3 mL), passed through a syringe filter, and purified by mass-directed preparative HPLC under basic conditions (5 mM NH4OH) to give the crude product as a brown glass-like solid. The crude solid was re-dissolved in MeOH (3 mL) and re-purified by UV-directed preparative HPLC under acidic conditions (0.1% TFA), collecting at 348 nm. The combined fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH) and the cartridge washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as an off-white glass-like solid (6 mg, 5% yield). LC-MS: Rt 0.52 mins; MS m/z 461.3/463.2 [M+H]+ [Method D]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (s, 1H), 7.95 (s, 1H), 7.32 (s, 1H), 7.15 (d, J=1.52 Hz, 1H), 4.35 (br. s., 1H), 3.87 (s, 3H), 3.01 (s, 3H), 1.65 (d, J=9.60 Hz, 2H), 1.48 (br. s., 2H), 1.22 (br. s., 6H), 1.11 (br. s., 6H).
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][C@@H:6]([C:11]([OH:13])=[O:12])[C:7]([SH:10])([CH3:9])[CH3:8].[CH3:14][N:15]([CH3:22])[C:16](=[O:21])[CH2:17][C:18]([CH3:20])=O>C(O)C>[CH3:8][C:7]1([CH3:9])[S:10][C:18]([CH2:17][C:16]([N:15]([CH3:22])[CH3:14])=[O:21])([CH3:20])[NH:5][CH:6]1[C:11]([OH:13])=[O:12]
Reactant: CC(=O)CC(=O)N(C)C
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)CC1(C)NC(C(=O)O)C(C)(C)S1
Yield: 76.1 %

Procedure:
In 40 ml of a mixture of chloroform and ethyl alcohol (1:1) were suspended 1.49 g (10 mmoles) of D-penicillamine and 1.89 g (15 mmoles) of N,N-dimethylacetoacetamide. The suspension was heated at 80°-90° C. with stirring under a stream of argon to concentrate to a half its volume. 20 ml of a mixture of chloroform and ethyl alcohol (1:1) was added. The concentration and addition of the solvent were repeated until the reaction mixture turned completely clear and a small amount of insolubles was removed by filtration. The solvent was distilled off, and the resulting residue was treated according to the same procedure as in Example 1 to give 1.98 g of 4-carboxy-2,5,5-trimethylthiazolidine-2-N,N-dimethylacetamide as colorless prisms.
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:24][C@H:25]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:40]2[C:45]([Cl:46])=[CH:44][N:43]=[C:42](Cl)[N:41]=2)(=[O:32])=[O:31])[CH2:26]1)(C)(C)C>>[Cl:46][C:45]1[C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[S:30]([N:27]2[CH2:28][CH2:29][C@H:25]([OH:24])[CH2:26]2)(=[O:31])=[O:32])=[N:41][C:42]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:43][CH:44]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: COc1cc2c(cc1N)CCN(C[C@@H](C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@H](O)C3)n1)CCN(C[C@@H](C)O)CC2
Yield: 29 %

Procedure:
In an analogous manner to Example 15N34, the product was prepared from (R)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol and {2-[(S)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. The product was isolated as a white solid (35 mg, 29%). mp: 199-201° C. MS (ESI+): 603 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.58-7.52 (m, 2H), 7.25 (t, J=8 Hz, 1H), 6.66 (s, 1H), 4.37 (br s, 1H), 3.88 (m, 4H), 3.42 (m, 3H), 3.31 (d, 1H), 2.91-2.52 (m, 10H), 2.27 (m, 1H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: O[C:2]1[C:3](O)=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11](O)=[O:12])[C:7](=[O:14])[C:6]=2[CH:15]=1.S(Cl)([Cl:19])=O>>[O:14]=[C:7]1[C:6]2=[CH:15][CH2:2][CH2:3][CH:4]=[C:5]2[S:10][CH:9]=[C:8]1[C:11]([Cl:19])=[O:12]
Reactant: O=C(O)c1csc2cc(O)c(O)cc2c1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1csc2c(c1=O)=CCCC=2

Procedure:
6,7-Dihydroxy-4-oxo-4H-1-benzothiopyran-3-carboxylic acid (100 mg) was heated under reflux for 2 hours in thionyl chloride (5 mL), and then the thionyl chloride was distilled off. To the residue was added benzene (20 mL). Benzene was distilled off again and the residue was vacuum dried to give 6,7-dihydro-4-oxo-4H-1-benzothiopyran-3-carbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[H-].[Na+].Cl[CH2:19][C:20]#[N:21]>CN(C=O)C>[C:20]([CH2:19][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:21]
Reactant: N#CCCl
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1CC#N
Reaction time: 8 h

Procedure:
A solution of 2-2 (11.2 g, 44.4 mmol) in DMF (400 mL) was treated with NaH (3.2 g of 60% dispersion in oil, 66.6 mmol) for 0.5 hour and then chloroacetonitrile (Aldrich, 5.6 mL, 88.8 mmol) was added and the reaction was stirred overnight. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The water layer was extracted with EtOAc, the organic layers were combined, washed with water, brine, dried with MgSO4, filtered and evaporated to give 2-3 as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:36]([O:37][CH2:38][CH:39]([F:41])[F:40])=[CH:35][C:14]3[N:15]([CH3:34])[C:16]([NH:18][C:19]4[CH:24]=[C:23]([CH2:25][NH:26][S:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[CH:22]=[CH:21][C:20]=4[Cl:33])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:47]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:36]([O:37][CH2:38][CH:39]([F:41])[F:40])=[CH:35][C:14]3[N:15]([CH3:34])[C:16]([NH:18][C:19]4[CH:24]=[C:23]([CH2:25][NH:26][S:27]([C:29]([CH3:31])([CH3:32])[CH3:30])(=[O:47])=[O:28])[CH:22]=[CH:21][C:20]=4[Cl:33])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Cn1c(Nc2cc(CNS(=O)C(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(Nc2cc(CNS(=O)(=O)C(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Temperature: 25 °C

Procedure:
A mixture of N-(4-bromo-phenyl)-2-(2-chloro-5-{[(tert-butylsulfinyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide (100 mg; 0.15 mmol), m-chloroperoxybenzoic acid (28 mg; 0.16 mmol) and DCM (20 mL) was stirred over night at rt. The mixture was basicified to pH ˜8-9 and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give the title compound. Yield: 24 mg (23%). 200 MHz 1H-NMR (DMSO-d6, ppm) 10.06-10.02 (1H, m) 7.75-7.62 (4H, m) 7.54-7.44 (4H, m) 7.27-7.17 (2H, m) 6.95-6.84 (1H, m) 6.57-6.49 (1H, m) 4.58-4.42 (2H, m) 4.16-4.09 (2H, m) 3.57-3.51 (3H, m) 1.29 (9H, s). MS m/z: 684, 686, 690 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24]([Cl:25])=[C:23](SC)[N:22]=[C:21](SC)[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.Cl>C(O)C.[Ni]>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]2[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][N:20]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc(NCC2CCN(C(=O)OCc3ccccc3)CC2)c(Cl)c(SC)n1
Agent: [Ni]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncncc2Cl)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-[(5-Chloro-2,6-bis-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (1.0 g, 2.2 mmol) was suspended in ethanol (15 mL) and ethyl acetate added to give a homogeneoussolhution, and excess Raney nickel was added. The resulting reaction mixture was stirred overnight. More Raney Nickel was added and the reaction mixture was heated to 80° C. for 3 h. The mixture was filtered and the solids were washed with hot ethanol/ethyl acetate several times. The organics were concentrated and the resulting residue was purified by silica gel chromatography (isopropanol/methylene chloride). The product was dissolved in ether and treated with ethereal HCl (2.2 mmol) to form the HCl salt which was collected by filtration. The resulting 4-[(5-chloro-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester hydrochloride salt was collected by filtration as a colorless solid.