Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH3:15])=[CH:7][C:6]=1[Si:16]([CH3:19])([CH3:18])Cl)[CH:2]=[CH2:3].[CH3:20][N:21]([CH3:30])[C:22]1([Li])[CH:26]=[C:25]([CH3:27])[C:24]([CH3:28])=[CH:23]1>C1(C)C=CC=CC=1.O1CCCC1>[CH3:20][N:21]([CH3:30])[C:22]1[CH:26]([Si:16]([C:6]2[CH:7]=[C:8]([CH3:15])[CH:9]=[C:10]([C:11]([CH3:13])([CH3:14])[CH3:12])[C:5]=2[O:4][CH2:1][CH:2]=[CH2:3])([CH3:19])[CH3:18])[C:25]([CH3:27])=[C:24]([CH3:28])[CH:23]=1
Reactant: [Li]C1(N(C)C)C=C(C)C(C)=C1
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)C1C(N(C)C)=CC(C)=C1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 102.7 %

Procedure:
A solution of (2-allyloxy-3-tert-butyl-5-methylphenyl)dimethylchlorosilane (7.0 mmol) in toluene (12.1 mL) was added dropwise to a solution of 1-dimethylamino-3,4-dimethylcyclopentadienyllithium (7.0 mmol) in tetrahydrofuran (10.5 mL) and the mixture was stirred at room temperature for 6 hours. After the solvent was distilled off under reduced pressure, dehydrated pentane was added and a precipitated solid was filtered off. The filtrate was concentrated to obtain the title compound (2.86 g, 100%) as an oil.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.NC(N)=[S:11].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1)([O-:15])=[O:14].[OH-].[Na+]>C(O)C.O>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][S:11][CH2:3][C:4]2[N:5]=[CH:6][NH:7][CH:8]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: NC(N)=S
Reactant: ClCc1c[nH]cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CSCc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.53 g (10 mmol) of 4-chloromethylimidazole hydrochloride and 0.76 g (10 mmol) of thiourea is brought to reflux in 10 ml of ethanol for 15 min. 5 ml of ethanol, 20 ml of water and 200 mg (1.16 mmol) of 4-nitrobenzyl chloride are added and the mixture is cooled to 0°-10° C. 1.44 g (36 mmol) of a solution of sodium hydroxide in 14 ml of water are added dropwise under nitrogen at 0°-10° C., and the mixture is then stirred for 1 hour at the same temperature and for a further 3 hours at room temperature. The abovementioned is collected and washed with water to provide the title compound, M.p.: 88° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1B(O)O.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]3[CH2:36][C@H:35]4[C@:37]5([CH2:41][N:40]([CH2:42][C:43]([F:46])([F:45])[F:44])[S:39](=[O:48])(=[O:47])[NH:38]5)[C@H:32]([CH2:33][CH2:34]4)[CH2:31][C:30]=3[CH:49]=2)O1>>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[N:5]1[CH:6]=[C:2]([C:26]2[CH:27]=[CH:28][C:29]3[CH2:36][C@H:35]4[C@:37]5([CH2:41][N:40]([CH2:42][C:43]([F:46])([F:45])[F:44])[S:39](=[O:47])(=[O:48])[NH:38]5)[C@H:32]([CH2:33][CH2:34]4)[CH2:31][C:30]=3[CH:49]=2)[N:3]=[CH:4]1
Reactant: Brc1c[nH]cn1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Product: O=S1(=O)N[C@@]2(CN1CC(F)(F)F)[C@@H]1CC[C@H]2Cc2ccc(-c3cn(-c4ccc(F)cc4F)cn3)cc2C1

Procedure:
Prepared from 4-bromo-1H-imidazole, 2,4-difluorophenylboronic acid and homochiral boronate from Example 24 Step 1 following the procedures in Example 76 Steps 1 and 2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:25][C@@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)=[N:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH:22]3[CH2:24][O:23]3)[CH:15]=2)=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:31][NH2:32]>CO>[CH3:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][CH2:21][CH:22]([OH:23])[CH2:24][NH:32][CH3:31])=[N:4][C:3]=1[NH:25][C@@H:26]1[CH2:30][CH2:29][O:28][CH2:27]1
Reactant: CN
Reactant: Cc1c(N[C@@H]2CCOC2)nc(-c2cccc(OCC3CO3)c2)nc1N1CCOCC1
Solvent: CO
Product: CNCC(O)COc1cccc(-c2nc(N[C@@H]3CCOC3)c(C)c(N3CCOCC3)n2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 37 %

Procedure:
5-Methyl-6-morpholino-2-(3-(oxiran-2-ylmethoxy)phenyl)-N—((R)-tetra-hydrofuran-3-yl)pyrimidin-4-amine (20 mg, 0.05 mmol) was dissolved in a 2N MeNH2 solution in methanol, (10 mL) and the mixture was stirred at room temperature for 14 h., concentrated under vacuum and the residue was purified by preparative HPLC to obtain the 1-(3-(5-methyl-4-morpholino-6-((R)-tetrahydrofuran-3-ylamino)pyrimidin-2-yl)phenoxy)-3-(methyl-amino)propan-2-ol (8 mg, 37% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm: 8.02-7.96 (m, 2H), 7.34 (t, J=8.0 Hz, 1H), 7.05-7.00 (m, 1H), 4.85-4.80 (m, 1H), 4.20-4.14 (m, 2H), 4.07-4.01 (m, 3H), 3.93-3.84 (m, 5H), 3.78-3.74 (m, 1H), 2.96-2.92 (m, 1H), 2.88-2.82 (m, 1H), 2.53 (s, 3H), 2.42-2.35 (m, 1H), 2.11-2.04 (m, 4H); ESI-LCMS (m/z): 444.3 [M+1]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:3]([OH:21])[CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[CH3:36][O:37][CH2:38][C:39]1[S:40][CH:41]=[C:42]([CH2:44][N:45]2[CH2:49][CH2:48][N:47]([C@@H:50]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:51](O)=[O:52])[C:46]2=[O:58])[N:43]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][C:51](=[O:52])[C@@H:50]([N:47]1[CH2:48][CH2:49][N:45]([CH2:44][C:42]2[N:43]=[C:39]([CH2:38][O:37][CH3:36])[S:40][CH:41]=2)[C:46]1=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: COCc1nc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)cs1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCc1nc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)C(C)(C)C)C2=O)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A solution of the product from Example 6A (0.034 g, 0.089 mmol) in THF (0.9 mL) was treated with the product from Example 6H (0.035 g, 0.103 mmol), DEPBT (0.040 g, 0.134 mmol), and N,N-diisopropylethylamine (0.075 mL, 0.431 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography using C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.047 g, 75% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[N:7]1.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([N:37]3[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]3)[CH:32]=[CH:31][CH:30]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=1
Reactant: Cc1cc(-c2nc(-c3ccc(C(C)(C)C(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Reactant: OC1CCNCC1
Product: Cc1cc(-c2nc(-c3ccc(C(C)(C)C(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCC(O)CC2)c1

Procedure:
Analogously to the process described in Example 9, 125 mg (0.247 mmol) of the compound from Example 3A and 50 mg (0.495 mmol) of 4-hydroxypiperidine were used to obtain 16 mg (12% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([Si:22]([CH3:32])([CH3:31])S(OC(F)(F)F)(=O)=O)([CH3:21])([CH3:20])[CH3:19]>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([O:10][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:32])[CH3:31])=[CH2:9])[N:7]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: CC(C)(C)[Si](C)(C)S(=O)(=O)OC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 1-(6-bromopyridin-2-yl)ethanone (1000 mg, 5.0 mmol) and triethylamine (2.1 mL, 15.0 mmol) at 0° C. in dichloromethane (14 mL) was added trifluoromethyl tert-butyldimethylsilanesulfonate (1.4 mL, 6.2 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified via flash chromatography (0-30% ethyl acetate in heptanes) to afford 2-bromo-6-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine as a colorless oil (1450 mg, 92%). 1H NMR (400 MHz, DMSO-d6) δ 0.22 (s, 6H), 0.98 (s, 9H), 4.62-4.63 (m, 1H), 5.52 (s, 1H), 7.56-7.62 (m, 2H), 7.82 (s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)(=[O:21])[CH3:20].[C:28](OCC)(=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[N:22]1([C:19](=[O:21])[CH2:20][C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(=O)N1CCOCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(=O)CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
10.2 g of diisopropylamine (0.1 mol) was placed in 100 ml dry THF under nitrogen and cooled in a freezing mixture. 40 ml n-butyllithium in hexane (2.5 M, 0.1 mol) was slowly added dropwise. When the addition was completed the mixture was allowed to stir for 60 minutes and then acetylmorpholine 12.9 g (0.1 mol) was added dropwise. The reaction mixture was stirred for 20 min in the freezing mixture. In a second flask, 43.7 g of diethyl oxalate (0.3 mol) in 50 ml of dry THF was cooled in a freezing mixture and the cooled reaction mixture was cannulated with stirring in small portions to it. It was left overnight under stirring to warm to room temperature. The THF was removed on a rotary evaporator and the residue was taken up in 80 ml half concentrated hydrochloric acid. The aqueous phase was extracted five times with 150 ml ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator to dryness. The excess diethyl oxalate was removed by distillation (2-3 mbar, 80° C.). 5.0 g of product were obtained in the form of white crystals with a melting point of 60° C. after crystallization from PE (petrol ether).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:25]O)[C:5]1=[O:30])[CH:2]=[CH2:3].[CH3:32][N:33]([CH3:38])[S:34]([NH2:37])(=[O:36])=[O:35]>>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([C@@H:24]([CH:27]3[CH2:29][CH2:28]3)[CH2:25][NH:37][S:34](=[O:36])(=[O:35])[N:33]([CH3:38])[CH3:32])[C:5](=[O:30])[C@@:4]([CH3:31])([CH2:1][CH:2]=[CH2:3])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C2CC2)C1=O
Reactant: CN(C)S(N)(=O)=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)N(C)C)C2CC2)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252, Step A) and N,N-dimethylsulfamide (TCI America, Portland, Oreg.) following a procedure similar to the one described in Example 202, Step C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1>CN(C)C=O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:21]1[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1
Reactant: Nc1ccccc1Br
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1ccccc1NC1C=CCCC1
Temperature: 75 °C
Yield: 70.4 %

Procedure:
To a solution of 2-bromoaniline (2.0 g, 12 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (2.4 g, 18 mmol) and 3-bromocyclohexene (2.7 mL, 23 mmol). The mixture was heated at 75° C. for 16 hours. The reaction was allowed to cool before being diluted with ethyl acetate (50 mL) and toluene (15 mL). The solution was washed with brine, dried over magnesium sulfate, and concentrated. The residue was dried under high vacuum to yield 2.13 g (73%) of N-(2-bromophenyl)-N-cyclohex-2-en-1-ylamine. 1H NMR (DMSO-d6): δ 7.40 (d, 1H), 7.16 (t, 1H), 6.79 (d, 1H), 6.53 (t, 1H), 5.83-5.88 (m, 1H), 5.66-5.71 (m, 1H); 4.43 (d, 1H), 4.06 (m, 1H), 1.99 (m, 2H), 1.82 (m, 1H), 1.60 (m, 3H). MS m/z 252, 254 (M+1).
Reaction SMILES: N1C=CN=C1.C1(OP(Cl)(Cl)=O)C=CC=CC=1.[C:17]([O:21][C:22]([NH:24][C@H:25]([C:33]([OH:35])=O)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl.[CH3:37][NH:38][O:39][CH3:40]>C(Cl)Cl>[CH3:40][O:39][N:38]([CH3:37])[C:33](=[O:35])[C@H:25]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:24][C:22]([O:21][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:23]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
To a solution of 44.2 g (0.65 mole) of imidazole in methylene chloride (300 ml) is added with stirring 19.4 ml (0.13 mole) of phenyldichlorophosphate. The mixture is stirred at room temperature for 0.5 hour, and then cooled to 0° C. A solution of 34.5 g (0.13 mole) of N-t-butoxycarbonyl-L-phenylalanine in 10 methylene chloride (120 ml) is added, and the mixture is stirred at 0° C. for 1 hr. N,O-dimethylhydroxylamine hydrochloride (15.2 g, 0,156 mole) is then added in small portions. The resulting mixture is stirred at 0° C. for 5 hours and at room temperature for 16 hours. The final suspension is diluted with 400 ml of methylene chloride, washed with 1N hydrochloric acid (2×200 ml), water (200 ml), saturated potassium carbonate solution (200 ml), and brine (200 ml), and dried over anhydrous magnesium sulfate. Removal of solvents gives 40.2 g of the title compound as a pale yellow oil, [α]D26 +22°±1 (c, 1.052, CHCl3).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.Br.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][NH:26][C:25](=[O:29])[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:29]=[C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][NH:20][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)[CH:28]=[CH:27][NH:26]1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: NCCc1cc[nH]c(=O)c1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(C(=O)NCCc3cc[nH]c(=O)c3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (100 mg, 0.4 mmol), 4-(2-aminoethyl)pyridin-2(1H)-one hydrobromide (96 mg, 0.44 mmol), HATU (182 mg, 0.48 mmol) and DIEA (155 mg, 1.20 mmol) in 30 mL of DCM was stirred at room temperature overnight. The solution was washed with sat NaHCO3 (2×30 mL), brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduce pressure to give crude N-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (160 mg) and used without further purification. LC-MS: 369 [M+H]+, tR=1.35 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([CH3:31])[CH:22]=1)=[O:19].C([O-])(O)=O.[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[C:23]([CH3:31])[CH:22]=2)=[O:19])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(NC(=O)OC(C)(C)C)C2)c2ccccc2n1
Temperature: 70 °C
Reaction time: 144 h

Procedure:
A mixture of pyrrolidin-3-yl-carbamic acid tert-butyl ester (10 mmol), 1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (10 mmol), NaHCO3 (20 mmol), Nal (0.5 mmol), and THF (70 mL) is stirred in a sealed vessel at 70° C. for 6 d. The reaction mixture is filtered, evaporated to dryness, and the residue is purified by preparative HPLC to provide the title compound.
Reaction SMILES: [Cl:1][C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[NH2:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[ClH:1].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:2](=[O:3])[O:4][CH:5]([Cl:7])[CH3:6])[CH2:10][CH2:11]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: NC1CCOCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)NC1CCOCC1
Product: Cl

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood, 1.32 g, 1.0 mL, 9.27 mmol) was reacted with 4-aminotetrahydropyrane (Oakwood, 899 mg, 0.92 mL, 8.62 mmol) and pyridine (782 mg, 0.8 mL, 9.89 mmol) in methylene chloride (20 mL) at −78° C. for 3 h to give 1-chloroethyl tetrahydro-2H-pyran-4-ylcarbamate compound with pyridine hydrochloride (1:1). A portion of this material (520 mg, 1.61 mmol) in dimethylformamide (5 mL) was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (151.4 mg, 0.246 mmol) and cesium carbonate (599.5 mg, 1.84 mmol) in dimethylformamide (4.00 mL) at room temperature for 17 h to give 1-(tetrahydro-2H-pyran-4-ylcarbamoyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (145.7 mg, 75% yield). MS (ES+) m/z calcd. for C39H42Cl2F2N4O7: [(M+H)+]: 787, found: 787
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].C(Cl)Cl.CCN(C(C)C)C(C)C.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(O)ccc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a 5 L round bottom flask fitted with an overhead stirrer, thermocouple and N2 inlet, was added 4-bromo-3-methoxyphenol (254 g, 1251 mmol), DCM (2500 mL) and DIPEA (437 mL, 2502 mmol). The reaction mixture was cooled in an ice bath, followed by addition of tert-butylchlorodimethylsilane (198 g, 1314 mmol). The reaction mixture was stirred at RT overnight, and then diluted with water. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to provide (4-bromo-3-methoxyphenoxy)(tert-butyl)dimethylsilane (472 g, 1250 mmol, 100% yield). MS (M+1)=319.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.[CH:19]1([C:23]2[N:24]=[C:25](/[CH:28]=[CH:29]/[C:30]3[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=3)[S:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([C:15]([NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30](/[CH:29]=[CH:28]/[C:25]3[S:26][CH:27]=[C:23]([CH:19]4[CH2:22][CH2:21][CH2:20]4)[N:24]=3)[CH:31]=2)=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reactant: COC(=O)c1ccccc1C1(C(=O)O)CCCC1
Product: COC(=O)c1ccccc1C1(C(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)CCCC1

Procedure:
In a manner analogous to Example 7a and 7b, when 2-(1-carboxycyclopentyl)benzoic acid methyl ester is reacted with (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, there is obtained (E)-2-[1-[[[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenyl]amino]carbonyl]cyclopentyl]benzoic acid methyl ester which is converted to (E)-2-[1-[[[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenyl]amino]carbonyl]cyclopentyl]benzoic acid.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[CH:10]([C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=1)=O>CCO>[OH:3][N:2]=[CH:10][C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(C=O)s1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COC(=O)c1ccc(C=NO)s1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Hydroxylamine hydrochloride (420 mg, 6.1 mmol) and pyridine (0.5 mL) were added to a solution of methyl 5-formylthiophene-2-carboxylate (690 mg, 4.1 mmol) in EtOH (25 mL). The reaction mixture was refluxed for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in diethyl ether, the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get product methyl 5-((hydroxyimino)methyl)thiophene-2-carboxylate (440 mg, yield 60%), which was carried through without any further purification. 1H NMR (400 MHz, DMSO-d6) δ 12.5 (s, 1H), 7.98 (s, 1H), 7.78 (d, J=4.1 Hz, 1H), 7.51 (d, J=4.1 Hz, 1H), 3.82 (s, 3H). MS (ESI) m/z: Calculated for C7H7NO3S: 185.01. found: 186.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14]([OH:16])=O)=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C:25]2=[O:30])=[CH:20][CH:19]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14](=[O:16])[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][C:25]2=[O:30])=[CH:22][CH:23]=1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]nc(C(=O)O)c2c1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2[nH]nc(C(=O)Nc3ccc(N4CCOCC4=O)cc3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 60 mg 1H-Indazole-3,5-dicarboxylic acid 5-methyl ester and 52 mg 4-(4-Amino-phenyl)-morpholin-3-one in 2 mL DCM, 68 mg BOP-Cl and 0.15 mL NEt3 were added and the mixture was stirred for 16 h at RT. Then after the reaction mixture was diluted with 20 mL DCM, the solution was washed with 15 mL of water. The organic phase was dried over MgSO4 and after filtration concentrated under reduced pressure. The crude product was subjected to the next reaction step without further purification. Yield: 71 mg.