Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:39])[N:10]([C@H:19]([C:21]2[N:30](COCC[Si](C)(C)C)[C:24]3=[N:25][CH:26]=[C:27](Br)[CH:28]=[C:23]3[N:22]=2)[CH3:20])COCC[Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:40]([C@@H:42]1[CH2:51][C:50]2[N:49]=[C:48]([CH3:52])[N:47]=[C:46]([N:53]3[CH2:59][C:58]4[CH:60]=[C:61](B(O)O)[CH:62]=[CH:63][C:57]=4[O:56][CH2:55][CH2:54]3)[C:45]=2[CH2:44][CH2:43]1)[CH3:41]>>[C:1]1([CH2:7][O:8][C:9](=[O:39])[NH:10][C@H:19]([C:21]2[NH:22][C:23]3[C:24]([N:30]=2)=[N:25][CH:26]=[C:27]([C:61]2[CH:62]=[CH:63][C:57]4[O:56][CH2:55][CH2:54][N:53]([C:46]5[C:45]6[CH2:44][CH2:43][C@H:42]([CH2:40][CH3:41])[CH2:51][C:50]=6[N:49]=[C:48]([CH3:52])[N:47]=5)[CH2:59][C:58]=4[CH:60]=2)[CH:28]=3)[CH3:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC[C@H]1CCc2c(nc(C)nc2N2CCOc3ccc(B(O)O)cc3C2)C1
Reactant: C[C@@H](c1nc2cc(Br)cnc2n1COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)OCc1ccccc1
Product: CC[C@H]1CCc2c(nc(C)nc2N2CCOc3ccc(-c4cnc5nc([C@H](C)NC(=O)OCc6ccccc6)[nH]c5c4)cc3C2)C1

Procedure:
Prepared according to the method of example 5 by using phenylmethyl{(1S)-1-[6-bromo-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethyl}({[2-(trimethylsilyl)ethyl]oxy}methyl)carbamate (reagent preparation 19) and {4-[(7S)-7-ethyl-2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.54 (br, 1H), 8.05 (br, 1H), 7.61 (s, 1H), 7.48 (d, 1H), 7.41 to 7.29 (m, 5H), 7.09 (d, 1H), 4.77 (d, 2H), 4.61 (d, 2H), 4.43 (m, 1H), 4.20 (m, 1H), 4.04 (m, 1H), 3.95 (m, 1H), 3.88 (s, 3H), 3.29 (m, 1H), 2.87 (m, 1H), 2.78 (m, 1H), 2.60 (m, 1H), 2.35 (s, 3H), 2.29 (m, 1H), 1.96 (m, 1H), 1.69 (m, 1H), 1.63 (d, 3H), 1.41 (m, 2H), 1.16 (m, 1H), 0.99 (t, 3H); MS (EI) for C36H39N7O3: 618 (MH+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH2:19][NH:18][C:17](=O)[CH2:16][O:15]2)=[CH:10][CH:9]=1.[OH-].[Na+]>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[O:15][CH2:16][CH2:17][NH:18][CH2:19]2)=[CH:12][CH:13]=1
Reactant: COc1cccc(C2(c3ccc(Br)cc3)CNC(=O)CO2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C2(c3ccc(Br)cc3)CNCCO2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a solution of LAH in THF (1M, 13.9 mL) at 0° C. was added a solution of 6-(4-bromo-phenyl)-6-(3-methoxy-phenyl)-morpholin-3-one (3.34 g, 9.23 mmol) in THF (15 mL). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 16 h. To the mixture was added H20 (6.2 mL) followed by addition of 15% aqueous NaOH (6.2 mL) and H20 (7 mL). The mixture was filtered through celite and the celite was washed with EtOAc (50 mL). The filtrate was dried over MgSO4 and concentrated to afford 2.82 g of 2-(4-bromophenyl)-2-(3-methoxy-phenyl)-morpholine. 1HNMR (400 MHz, CDCl3) δ 7.43-7.36 (comp, 2H), 7.33-7.20 (comp, 3H), 6.98-6.82 (comp, 2H), 6.79-6.75 (m, 1 H), 3.76 (s, 3H), 3.68-3.69 (comp, 2H), 3.45-3.29 (comp, 2H), 2.93-2.88 (comp, 2H); MS (M+1) 348.01, 350.0.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:17]([NH:19][CH2:20][C:21]([NH:23][CH:24]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[O:18])[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>O.C(#N)C>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:17]([NH:19][CH2:20][C:21]([NH:23][CH:24]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[O:18])[CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)Nc2ccccc2)c1)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)Nc2ccccc2)c1)c1cccnc1
Temperature: 25 °C

Procedure:
The compound of Example 107 (500 mg, 0.095 mmol) was dissolved in water/acetonitrile (1:1), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) trifluoroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) to result in a white solid (350 mg). MS and 1H-NMR were consistent with proposed structure.
Reaction SMILES: N[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C1C(=O)N([Cl:19])C(=O)C1.N(OCCC(C)C)=O>C(#N)C>[Cl:19][C:4]1[S:3][CH:2]=[N:6][C:5]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1csc(N)n1
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)c1ncsc1Cl
Yield: 84.8 %

Procedure:
21 g (123 mmol) ethyl 2-aminothiazol-4-carboxylate (Example 30, step 1) was added to 150 ml acetonitrile, and 18.4 g (137 mmol) NCS was added portionwise, to carry out reaction at room temperature overnight; and then, 19 ml (137 mmol) isoamyl nitrite was added rapidly dropwise, followed by continuing the reaction for 2 hr after complete of addition. The resultant reaction mixture was concentrated, then ethyl acetate and water were added, and filtered to remove insoluble solids. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 20 g ethyl 5-chlorothiazol-4-carboxylate 1H NMR (CDCl3) 1.42-1.45 (3H, t, J=7.0 Hz); 4.43-4.46 (2H, m, J=7.0 Hz); 8.68 (1H, s); MS (EI) 191.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10](Cl)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.N1([C:23]2[C:24](=[O:38])[N:25]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH:28]=2)CCOCC1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:11]([C:10]1[C:28]2[CH2:27][CH2:26][N:25]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)[C:24](=[O:38])[C:23]=2[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)=[O:12])[CH3:15]
Reactant: O=C1C(N2CCOCC2)=CCCN1c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(Cl)=NNc1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 80 °C
Yield: 47.6 %

Procedure:
Part A: A 500 mL flask was charged with N-(3-chlorophenyl)-1-(ethoxycarbonyl)-methanehydrazonoyl chloride (3.67 g, 14.1 mmol), 3-morpholin-4-yl-1-(4-nitro-phenyl)-5,6-dihydro-1H-pyridin-2-one (2.14 g, 7.05 mmol), 50 mL of toluene, and triethylamine (3.57 g, 35.3 mmol). The mixture was heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was treated with trifuloroacetic acid (10.1 g) at rt for 5 h. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in methylene chloride, washed water and brine, and dried with sodium sulfate. The crude product, after evaporation of the solvent, was purified by silica gel chromatography, eluting with 1:2 ethyl acetate/hexane to yield 1-(3-chloro-phenyl)-6-(4-nitro-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (1.48 g). 1H NMR (300 MHz, CDCl3) δ 8.24 (2H, d, J=9.1 Hz), 7.60 (1H, t, J=1.8 Hz), 7.52 (2H, d, J=9.1 Hz), 7.47˜7.36(2H, m), 4.48 (2H, q, J=7.0 Hz), 4.22 (2H, t, J=6.6 Hz), 3.39 (2H, t, J=6.6 Hz), 1.45 (3H, t, J=7.0 Hz) ppm.
Reaction SMILES: C(N[CH2:5][CH2:6][CH2:7][S:8]([OH:11])(=[O:10])=[O:9])C#C.[Na+].C(OCC([O-])=O)C#C.[Na+].C(OC(C)C([O-])=O)C#C.[CH2:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38]S([O-])(=O)=O)C#C.[Na:43]>>[CH2:35]([O:34][CH2:31][CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=[O:9])=[O:10])[CH2:36][C:37]#[CH:38].[Na:43]
Reactant: C#CCOCCCCS(=O)(=O)[O-]
Reactant: C#CCNCCCS(=O)(=O)O
Agent: C#CCOC(C)C(=O)[O-]
Agent: C#CCOCC(=O)[O-]
Agent: [Na+]
Product: C#CCCOCCCCS(=O)(=O)[O-]

Procedure:
3-(prop-2-ynyloxy)-propyl-1-sulfonate-sodium salt; 3-(prop-2-ynylamino)-propane-1-sulfonic acid; 2-(prop-2-ynyloxy)-acetate sodium salt; 2-(prop-2-ynyloxy)-propanoate sodium salt; 4-(prop-2-ynyloxy)-butane-1-sulfonate-sodium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][C:22]5[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[C:23]=5[N:24]=4)[C:15](=[O:30])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:31]=1.S(=O)(=O)(O)O.[N-:37]=[N+]=[N-].[Na+].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][C:22]5[CH2:28][CH2:27][CH2:26][NH:37][C:25](=[O:29])[C:23]=5[N:24]=4)[C:15](=[O:30])[CH2:14]3)(=[O:11])=[O:12])[S:7][C:6]=2[CH:31]=1
Reactant: O=C1CCCc2sc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)nc21
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C1NCCCc2sc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)nc21

Procedure:
2-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-6,7-dihydro-5H-benzothiazol-4-one (60 mg, 0.12 mmol) is dissolved in CHCl3 (4 mL) and sulfuric acid (0.5 mL) is added with vigorous stirring. Sodium azide (25 mg 0.4 mmol) is added and the reaction is stirred 1¾ h. The reaction is then added dropwise to a rapidly stirring mixture of K2CO3/H20/CH2Cl2. The organic phase is separated and washed with water, dried (MgSO4) and concentrated. The residue is purified by column chromatography (silica, 2% to 6% MeOH/CH2Cl2) to provide a mixture of two products.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]3[N:9]([N:14]=[C:15]([NH2:17])[N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)[CH:20]=1.C(Cl)Cl>C(Cl)Cl.CO>[O:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:8]3[N:9]([N:14]=[C:15]([NH:17][CH:28]4[CH2:29][CH2:30][N:25]([C:21]5[CH:20]=[C:19]([CH3:18])[N:24]=[CH:23][N:22]=5)[CH2:26][CH2:27]4)[N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)[CH2:5][CH2:6]1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Reactant: Cc1cc(C2=CCOCC2)c2nc(N)nn2c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C2=CCOCC2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1

Procedure:
Prepared in analogy to example 1h, starting from 8-(3,6-dihydro-2H-pyran-4-yl)-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b). The title compound was obtained as a yellow oil (yield: 5%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent. MS ISP (m/e): 406.5 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([F:23])[CH:14]=[C:15]([CH:20]4[CH2:22][CH2:21]4)[CH:16]=3)[C:11]2=[O:24])[C:3]=1[CH:4]=[O:5].[Li+].[B-](CC)(CC)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[C:6]([N:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([F:23])[CH:14]=[C:15]([CH:20]4[CH2:22][CH2:21]4)[CH:16]=3)[C:11]2=[O:24])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1c(Cl)cccc1-n1ccc2cc(C3CC3)cc(F)c2c1=O
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1c2c(F)cc(C3CC3)cc2ccn1-c1cccc(Cl)c1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a suspension of compound III (0.26 g, 0.76 mmol) in 15 ml dry THF which was cooled at 0° C. in an ice bath, was added a solution of superhydride 1M (1.5 ml, 1.5 mmol) in THF. After stirring for 0.5 hour at 0° C. the reaction was quenched with saturated ammonium chloride and diluted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated to give 0.25 g (96% yield) of IV which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[S:10])[NH:8][CH:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH3:14]I.Cl>>[C:1]([C:4]1[C:5](=[O:11])[NH:6][C:7]([S:10][CH3:14])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)c1c[nH]c(=S)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CSc1ncc(C(C)=O)c(=O)[nH]1
Temperature: 40 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
5-Acetyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (Ryan Scientific) (2.3 g, 13.51 mmol) was dissolved in NaOH (20.27 mL, 20.27 mmol), then MeI (0.894 mL, 14.30 mmol) was added to the reaction mixture while stifling. The reaction mixture was heated at 40° C. for 1.5 hours. Additional MeI (0.894 mL, 14.30 mmol) was added and the reaction was allowed to stir at rt for 18 hours. The reaction mixture was cooled with an ice-water bath, acidified to pH 6 with concentrated HCl solution, then the resulting precipitate was filtered to obtain 1.72 g of the desired product (69% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.49 (br. s., 6 H) 8.35 (s, 1 H) 13.40 (br. s., 1 H). MS (ES+): m/z=185.1 (100) [MH+]. HPLC: tR=1.0 minute over 3 minutes. Purity: >90% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.[C:24](Cl)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)=[C:4]([CH:3]=1)[CH2:22][NH:23][C:24](=[O:25])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CNC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (500 mg, 0.89 mmol) and TEA (360 mg, 3.6 mmol) in THF (200 mL) at −20° C. was slowly added CbzCl (151 mg, 0.89 mmol) in THF (10 mL). Then the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 15%-40%, 25 min) to give the title compound (220 mg, 42%) as TFA salt. 1H NMR: DMSO 400 MHz δ 9.97 (s, 1H), 7.63 (t, J=7.2 Hz, 1H), 7.55 (q, 1H), 7.42 (q, 1H), 7.37 (q, 3H), 7.32 (q, 3H), 7.30 (q, 3H), 6.52 (s, 1H), 6.37 (q, 1H), 5.05 (s, 2H), 4.83 (s, 2H), 4.53 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([O:21]CC)=[O:20])[C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([OH:21])=[O:20])[C@H:13]([C:15]([F:16])([F:17])[F:18])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]([C@H](NC(=O)OCc1ccccc1)C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.15 g (6.45 mmol) of ethyl (3R)—N-[(benzyloxy)carbonyl]-4,4,4-trifluorovalinate (diastereomer mixture) were dissolved in a mixture of in each case 8 ml of THF, methanol and water, and 3.87 g (96.8 mmol) of sodium hydroxide were added at 0° C. Ice-cooling was removed and the reaction mixture was stirred at RT for 1 h. The mixture was then added to water, acidified with semiconcentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. This gave 1.95 g of the target product which was not purified any further (99% of theory, diastereomer ratio about 2.8:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([N:24]=[C:25]=[S:26])[CH2:5][O:6][Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:28][CH:29]1[CH2:32][NH:31][CH2:30]1>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH:24][C:25]([N:31]1[CH2:32][CH:29]([OH:28])[CH2:30]1)=[S:26])[CH2:5][O:6][Si:7]([C:20]([CH3:23])([CH3:21])[CH3:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N=C=S
Reactant: OC1CNC1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=S)N1CC(O)C1
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of 3-(t-butyldiphenylsilyloxy)-2-isothiocyanatopropionic acid methyl ester (13.4 g, 33.5 mmol) (obtained as described in Reference Example 70(1)) in tetrahydrofuran (245 ml) was added a solution of 3-hydroxyazetidine (4.90 g, 67.1 mmol) (obtained as described in Reference Example 31(1)) in water (50 ml) at room temperature and the mixture was stirred overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene and toluene:acetonitrile (3:1) as the eluant to afford (2S)-3-(t-butyldiphenylsilyloxy)-2-[(3-hydroxyazetidine-1-carbothioyl)amino]propionic acid methyl ester (9.60 g, yield 61%) as an yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][N:8]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)([C:14]#[N:15])[CH3:13])[N:9]=2)[CH:5]=[C:4]([Cl:30])[CH:3]=1.[F-].[K+].[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:30][C:4]1[CH:3]=[C:2]([C:38]2[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=2)[C:10]2[C:6]([CH:5]=1)=[N:7][N:8]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([C:14]#[N:15])[CH3:13])[N:9]=2
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C#N)(Cn1nc2cc(Cl)cc(Br)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2cc(Cl)cc(-c3ccc(C(F)(F)F)cc3)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-[2-(4-Bromo-6-chloro-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (120 mg) described in Example 38, bis(tri-t-butylphosphine)palladium (20 mg), bis(dibenzylideneacetone)palladium (20 mg), potassium fluoride (42 mg) and 4-trifluoromethylphenyl boronic acid (45 mg) in THF were stirred at room temperature for 3 days. The mixture was concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford a one to one mixture of title compound and starting material [110 mg, Rf=0.3 (3:7 EA/heptane)]. This mixture was further purified by semi-preparative liquid chromatography (methanol/water) to afford the title compound as pure solid (35 mg, 26%). MS (ES): M/Z [M+H]=568. NMR: (400 MHz, DMSO-d6): 1.74 (s, 3H), 1.84 (s, 1H), 5.39 (d, J=13.3 Hz, 1H), 5.64 (d, J=13.3 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.84 (d, J=1.8 Hz, 1H), 7.93 (d, J=8.9 Hz, 2H), 8.12 (d, J=8.1 Hz, 2H) and 8.23 (d, J=1.8 Hz, 1H). 19F NMR (376 MHz, DMSO-d6): −61.8 (s, 3F) and −57.3 (s, 3F).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[N-:13]=[C:14]=[O:15].[K+]>O.C(O)(=O)C>[NH:1]([C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)[C:14]([NH2:13])=[O:15]
Reactant: [N-]=C=O
Reactant: Nc1ccc(/C=C/C(=O)O)cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc(/C=C/C(=O)O)cc1
Temperature: 100 °C
Yield: 79.5 %

Procedure:
A stirred solution of (E)-3-(4-aminophenyl)acrylic acid (1.0 g, 5.0 mmol) and potassium isocyanate (2.0 g, 5 equiv.) in a mixture of water and acetic acid (50 mL) was heated at 100° C. for 12 hours. After cooling, a white solid precipitated out. Filtration, washing of the filter cake with a mixture of water and MeOH, and drying it in vacuo gave the title compound (0.82 g, 80%) as a white solid.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25].CCN(C(C)C)C(C)C.[F:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][C@@H:37]([F:36])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25]
Reactant: F[C@@H]1CCNC1
Reactant: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)CCC1(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@@H](F)C4)ccc23)CCC1(F)F

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-fluoro-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.66 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.56 (m, 1H), 1.27-1.32 (m, 1H), 1.00 (d, 3H). m/z: 456 [M+H]
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N1CCNCC1)C.C(=O)([O-])[O-:29].[K+].[K+]>CN(C)C=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[NH:3][C:2](=[O:29])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Reactant: O=C([O-])[O-]
Agent: CCN1CCNCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Yield: 123 %

Procedure:
A mixture of 1-chloro-3-(4-methoxyphenyl)isoquinoline (0.89 g), N-ethylpiperazine (0.86 g) and potassium carbonate (1.10 g) was heated in dimethylformamide (20 ml) at 90° C. for 12 hr. The reaction mixture was evaporated, water was added to the resulting residue, and then it was extracted with ethyl acetate. The resulting organic layer was washed with water and brine, dried over magnesium sulfate, and then the solvent was romoved. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound as a pale brown oil (1.02 g, yield; 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C@H:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C@H:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: C=CC[C@H](C)Oc1ccc(C)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1ccc(C)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of (S)-methyl 5-methyl-2-(pent-4-en-2-yloxy)benzoate (1.2664 g, 5.41 mmol) in THF (15 ml) cooled to 0° C. was added dropwise lithium aluminum hydride (3.25 ml, 6.49 mmol). The mixture was stirred at rt for 2 h then cooled to 0° C. and quenched by the dropwise addition of brine. The mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to give (S)-(5-methyl-2-(pent-4-en-2-yloxy)phenyl)methanol (0.8702 g, 4.22 mmol, 78% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.14-7.01 (m, 2H), 6.80 (d, J=8.1 Hz, 1H), 6.01-5.74 (m, 1H), 5.24-5.04 (m, 2H), 4.76-4.64 (m, 1H), 4.64-4.56 (m, 1H), 4.51 (sxt, J=6.0 Hz, 1H), 2.63-2.48 (m, 2H), 2.48-2.41 (m, 1H), 2.30 (s, 3H), 1.37 (d, J=6.1 Hz, 3H).