Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.[CH3:24][CH:25]([NH2:27])[CH3:26]>>[CH:25]([NH:27][C:21]([C:20]1[C:13]2[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[S:3][C:4]=4[CH:10]=3)=[N:17][CH:16]=[N:15][C:14]=2[NH:18][CH:19]=1)=[O:22])([CH3:26])[CH3:24]
Reactant: O=C(O)c1c[nH]c2ncnc(Nc3ccc4[nH]c(=O)sc4c3)c12
Reactant: CC(C)N
Product: CC(C)NC(=O)c1c[nH]c2ncnc(Nc3ccc4[nH]c(=O)sc4c3)c12

Procedure:
18.7 mg (57 μmol) 4-[(2-Oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (prepared according to example 3) were transformed in analogy to example 4 using propan-2-amine to give after working up and purification 3.2 mg (14%) of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[N:38]O)[NH2:37])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:38]=[C:26]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:37]=2)=[CH:32][CH:31]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1ccc(F)cc1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccc(F)cc3)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 42.3 (0.275 mmol) of 4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 59.1 mg (46% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:39])[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:22]2[CH:32]=[C:33]([Br:36])[CH:34]=[CH:35][C:21]=2[N:20]([CH3:37])[C:19]1=[O:38])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:39])[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:22]3[CH:32]=[C:33]([Br:36])[CH:34]=[CH:35][C:21]=3[N:20]([CH3:37])[C:19]2=[O:38])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2F)c2cc(Br)ccc2N(C)C1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2ccccc2F)c2cc(Br)ccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-D), the title compound was prepared as a white solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.[CH2:18]([O:25][C:26]1[N:31]=[C:30]([C:32]#[N:33])[C:29](Br)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]2[C:30](=[C:32]([NH2:33])[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=2)[N:31]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1nc(OCc2ccccc2)ccc1Br
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1nc2ccccc2c2ccc(OCc3ccccc3)nc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 6-(benzyloxy)-3-bromopicolinonitrile (from step 1) (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexane to give 3-(benzyloxy)benzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (acetone d-6): δ 8.95 (d, 1H), 8.35 (d, 1H), 7.58-7.63 (m, 2H), 7.49-7.53 (dd, 1H), 7.30-7.44 (m, 5H), 6.61 (br, 2H), 5.64 (s, 2H). LRMS [M+H]=302.1
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:14]([C:16]1[CH:28]=[C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[C:26]([O:34][CH3:35])=[CH:25][C:17]=1[O:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=O>>[CH3:35][O:34][C:26]1[C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:28][C:16](/[CH:14]=[CH:2]/[C:1](=[O:3])[C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[C:17]([CH:25]=1)[O:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21]
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OC(C)(C)C(=O)O)c(C=O)cc1-c1cccs1
Product: COc1cc(OC(C)(C)C(=O)O)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Yield: 85 %

Procedure:
The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 2-(2-formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-2-methyl-propionic acid (Ex-59B) in a similar manner as described in Ex-22. Yellow solid, mp 164–165° C., 85% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.21–8.28 (m, 3H), 7.96–8.12 (m, 4H), 7.67 (d, 1H, J=3.0 Hz), 7.56 (brs, 3.0H), 7.14 (dd, 1H, J=5.7, 3.0 Hz), 6.57 (s, 1H), 3.88 (s, 3H), 1.66 (s, 6H). MS (ESI) m/z=502 ([M+H]+, 100%). Anal. Calcd. for C24H23NO7S2: C, 57.47; H, 4.62; N, 2.79; S, 12.79. Found: C, 57.70; H, 4.74; N, 2.85; S, 12.51.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]=[CH2:32])=[CH:27][N:26]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:32][CH2:31][C:28]3[CH:27]=[N:26][C:25]([CH3:24])=[CH:30][CH:29]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc([N+](=O)[O-])cc1)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-8-methyl-2-(4-nitrophenyl)-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][C:5]([CH3:18])([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH3:18][C:5]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][O:6]1
Reactant: CC1(C(=O)OCc2ccccc2)CCC(O)CO1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C(=O)OCc2ccccc2)CCC(=O)CO1
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.8 %

Procedure:
To a mixture of benzyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate (1.1 g, 3.52 mmol) and molecular sieves (4 Å, 2 g, powdered) in DCM (20 mL) was added PCC (1.137 g, 5.27 mmol) in two portions at 0° C. The reaction mixture was stirred at rt for 17 h. The reaction mixture was directly loaded and purified on a 40 g silica gel cartridge (EtOAc/Hexane: 0 to 40%) to yield benzyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate (0.47 g). 1H NMR (400 MHz, CDCl3) ppm 7.45-7.31 (m, 5H), 5.25 (s, 2H), 4.27 (d, J=17.6 Hz, 1H), 4.07 (d, J=17.3 Hz, 1H), 2.59-2.34 (m, 3H), 2.14-2.04 (m, 1H), 1.56 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[CH:24](=O)[CH2:25][CH:26]([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]=[CH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CC(C)CC=O
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N
Product: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N=CCC(C)C

Procedure:
The present compound was synthesized by a method similar to that in Example 210 and using 2-amino-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (210 mg) and isovaleraldehyde. A colorless powder (95 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[O:17]=[C:18]([N:37]1[CH2:42][CH2:41][C:40]([CH2:43][C:44]2[S:45][CH:46]=[CH:47][N:48]=2)=[CH:39][CH2:38]1)/[CH:19]=[CH:20]/[C:21]1[CH:22]=[C:23]2[C:33](=[N:34][CH:35]=1)[NH:32][C:31](=[O:36])[C:25]1([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH2:24]2.[C:49](O)(=[O:52])[CH2:50][OH:51].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[OH:52][CH2:49][C:50]([N:28]1[CH2:29][CH2:30][C:25]2([CH2:24][C:23]3[C:33](=[N:34][CH:35]=[C:21](/[CH:20]=[CH:19]/[C:18](=[O:17])[N:37]4[CH2:42][CH2:41][C:40]([CH2:43][C:44]5[S:45][CH:46]=[CH:47][N:48]=5)=[CH:39][CH2:38]4)[CH:22]=3)[NH:32][C:31]2=[O:36])[CH2:26][CH2:27]1)=[O:51]
Reactant: O=C(/C=C/c1cnc2c(c1)CC1(CCNCC1)C(=O)N2)N1CC=C(Cc2nccs2)CC1
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1cnc2c(c1)CC1(CCN(C(=O)CO)CC1)C(=O)N2)N1CC=C(Cc2nccs2)CC1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 22.5 %

Procedure:
DIPEA (0.38 mL, 2.13 mmol) was added to a stirred solution of (E)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naph-thyridine-3,4′-piperidin]-2(4H)-one 2,2,2-trifluoroacetate (Compound 34) (200 mg, 0.35 mmol), Glycolic acid (80 mg, 1.06 mmol), HOBt (96 mg, 0.70 mmol) and EDC.HCl (170 mg, 0.88 mmol) in dry DMF (4 mL) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 4% methanol/dichloromethane as an eluent to get the desired compound as a light yellow solid (40 mg, 22%); 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.09 (s, 1H), 7.71 (d, J=3.4 Hz, 1H), 7.61 (d, J=3.5 Hz, 1H), 7.45 (d, J=15.7 Hz, 1H), 7.28-7.14 (m, 1H), 5.68-5.66 (m, 1H), 4.50 (t, J=5.4 Hz, 1H), 4.28-4.22 (m, 1H), 4.10-4.04 (m, 3H), 3.78-3.74 (m, 3H), 3.74-3.62 (m, 3H), 3.54-3.38 (m, 2H), 2.96 (s, 2H), 2.20-2.06 (m, 2H), 1.86-1.68 (m, 2H), 0.46-0.32 (m, 2H); ES-MS: 508.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[NH2:15][OH:16]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8](=[N:15][OH:16])[NH2:9]
Reactant: CS(=O)(=O)Nc1ccc(C#N)c(Cl)c1
Reactant: NO
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(C(N)=NO)c(Cl)c1
Temperature: 90 °C

Procedure:
To a stirred solution of the product from Step A (0.13 g, 0.565 mmol) in ethanol (3 mL) was added hydroxylamine (50% in water, 1.0 mL). The reaction was heated at 90° C. for 2 h. The reaction was then concentrated to give the desired product.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.C(N(CC)CC)C.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>ClCCl>[CH2:19]([S:21]([NH:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])(=[O:23])=[O:22])[CH3:20]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N[C@@H](CC(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A stirred solution of 3.0 g of H-Leu-OMe.HCl in 30 mL of dichloromethane was adjusted to pH 8 using triethylamine and cooled at 0° C. Then 3.2 mL of ethanesulfonyl chloride and 2.3 mL of triethylamine were added. After stirring for 16 h at room temperature the reaction mixture was washed successively with 0.5 N hydrochloric acid, water and aqueous 5% sodium hydrogencarbonate and concentrated. The crude product was purified by chromatography on silica gel (eluent: dichloromethane/methanol=9/1 v/v) to yield 3.3 g of EtSO2-Leu-OMe.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH:22]1[C:26]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)=[N:25][N:24]=[N:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([C:26]4[NH:25][N:24]=[N:23][N:22]=4)=[CH:28][CH:29]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Product: CC(C(=O)Nc1ccc(-c2nnn[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
65 mg (purity 83%, 0.18 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 1.2 eq. of 4-(1H-tetrazol-5-yl)aniline were reacted according to General Method 1. Yield: 17 mg (22% of theory)
Reaction SMILES: [BH4-].[Na+].[CH2:3]1[CH2:7][O:6][CH2:5][CH2:4]1.[Br:8][C:9]1[CH:14]=[CH:13]C=[CH:11][C:10]=1CCC(O)=O.B(F)(F)F.CCOCC>CC(OC)(C)C.O>[Br:8][C:9]1[CH:14]=[CH:13][C:5]([CH2:4][CH2:3][CH2:7][OH:6])=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: O=C(O)CCc1ccccc1Br
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: COC(C)(C)C
Product: OCCCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Sodium borohydride (119.12 g) and THF (5 L) were charged into reactor 1 and temperature adjusted to −20° C. 3-(bromophenyl)propionic acid (1 kg) was charged into reactor 2 with THF (3 L) and stirred at 25° C. until all the solids dissolved. This solution in reactor 2 was transferred to reactor 1 maintaining reactor 1 contents at <0° C. BF3.Et2O (991.4 g) was slowly added into reactor 1 maintaining reactor 1 contents at −20 to −10° C. After addition, the mixture was stirred at −20 to −10° C. for 1 h. The reaction is analysed for completion (3-(bromophenyl)propionic acid <2.5%). Water (2 L) was slowly added into reactor 1 to quench the reaction. (gas evolution). MTBE (5 L) was charged into reactor 1 and phases separation was carried out. The upper layer was collected and lower layer was washed with MTBE (5 L). The upper layer was collected and combined with the layer from the previous step. Adjusted pH value of the organic layer to 8-9 by adding 1N NaOH solution. The organic layer was washed with saturated NaCl solution (2 L) and the upper layer was collected. The organic layer was evaporated down to a colourless oil.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:29][CH:28]([CH2:30][C:31](OC)=[O:32])[CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31](=[O:32])[CH2:30][CH:28]5[CH2:29][O:26][CH2:27]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: COC(=O)CC1COC1
Agent: Cl
Product: O=C(CC1COC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (22.9 mg, 76.3%), MS (ISP) m/z=429.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and methyl 2-(oxetan-3-yl)acetate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][C@@H:30]([CH3:58])[C@@H:31]([NH:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[C:51]([Cl:57])[CH:50]=1)[C:32]([NH:34][NH:35][C:36](=[O:47])[C:37]1[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1)=O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[Si:22]([O:29][C@@H:30]([CH3:58])[C@@H:31]([NH:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[C:51]([Cl:57])[CH:50]=1)[C:32]1[O:47][C:36]([C:37]2[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=2)=[N:35][N:34]=1)([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:24])[CH3:23]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)c1nnc(-c2ccc(S(C)(=O)=O)cc2)o1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Polymer supported triphenylphosphine (2.08 g, 6.24 mmol) was diluted in 200 ml of DCM followed by addition of I2 (1.58 g, 6.24 mmol) and TEA (2.31 mL, 16.64 mmol) at 0° C. N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyanophenylamino)butanoyl)-4-(methylsulfonyl)benzohydrazide (2.35 g, 4.16 mmol) in 200 mL DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to warm to room temperature and stirred for an additional 10 min. The reaction was quenched with 55 mL saturated sodium thiosulfate and the biphasic mixture was separated. The aqueous layer was extracted with EtOAc (3×70 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography (SiO2) [EtOAc-hexanes (1:2), then (1:1) as eluent] to provide the title compound (2.16 g, 95%). The crude material was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]=[CH:5]2.CN(C)P(N(C)C)(N(C)C)=O.[CH3:23][CH2:24][CH2:25]CCC.C([Li])CCC.C(I)(C)C>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH:24]([CH3:25])[CH3:23])[CH2:5]2
Reactant: O=C1C=Cc2cc(Br)ccc21
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: CC(C)I
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C1Cc2cc(Br)ccc2C1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 100 mg of 5-bromo-1-oxoindene was dissolved in 2 ml of tetrahydrofuran, and cooled down to −78° C. 0.4 ml of hexamethylphosphoramide, 0.3 ml of 1.57 M n-butyllitium hexane solution, and 1.0 ml of isopropyl iodide were added, and the mixture was stirred at −78° C. for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by preparative thin-layer chromatography (ethyl acetate/hexane=1/2) to obtain 26 mg of the above compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:22]4[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])=[C:24]([F:37])[C:23]=4[CH3:38])[CH:19]=[CH:20][CH:21]=3)=[CH:13][C:8]=2[O:7][CH2:6]1.CO.[OH-].[Na+].Cl>O.O1CCCC1>[F:37][C:24]1[C:23]([CH3:38])=[C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][O:14][C:12]3[CH:11]=[CH:10][C:9]4[C@H:5]([CH2:4][C:3]([OH:39])=[O:2])[CH2:6][O:7][C:8]=4[CH:13]=3)[CH:17]=2)[C:27]([CH3:28])=[CH:26][C:25]=1[O:29][CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:34])=[O:35]
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)c(F)c4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(OCCCS(C)(=O)=O)c(F)c(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a solution of methyl[(3S)-6-({3′-fluoro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.418 g, 0.740 mmol) in a mixed solvent of methanol (4 mL) and tetrahydrofuran (8 mL) was added 2 M aqueous sodium hydroxide solution (2 mL, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-100:0), and the obtained crystals were recrystallized from hexane-ethyl acetate to give the title compound (0.248 g, yield 62%) as colorless crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:20]#[N:21])=[CH:15][CH:14]=1.C1C[O:30]CC1.C(=O)(O)[O-].[Na+]>Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:20]([NH2:21])=[O:30])=[CH:17][CH:18]=1
Reactant: N#CC(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Reactant: C1CCOC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: NC(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2 g (5.8 mmol) of the compound from Example II are suspended in 6 ml of concentrated hydrochloric acid, and the suspension is stirred at 40° C. overnight. After cooling to room temperature, THF is added until solution is complete, and the solution is neutralised with sodium bicarbonate solution. The organic phase is separated off, dried with sodium sulphate and concentrated to a small volume in vacuo. Separation is carried out by column chromatography (silica gel 60, mobile phase: dichloromethane/ethyl acetate/glacial acetic acid 80/15/15).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:27][CH2:26][C:13]3([C:18]4=[CH:19][CH:20]=[CH:21][N:17]4[C:16]4[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=4[O:14]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[S:28]([CH3:31])(=[O:30])=[O:29].[CH3:32][OH:33].[H-].[Na+]>CN(C=O)C>[CH3:32][O:33][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:27][CH2:26][C:13]3([O:14][C:15]4[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=4[N:17]4[CH:21]=[CH:20][CH:19]=[C:18]34)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[S:28]([CH3:31])(=[O:30])=[O:29]
Reactant: CO
Reactant: CS(=O)(=O)c1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1S(C)(=O)=O
Reaction time: 0.17 h

Procedure:
(4-Fluoro-3-methylsulfonyl-phenyl)-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl-methanone (44 mg, 0.10 mmol) and MeOH (12 μL, 0.30 mmol) were combined in DMF (1 mL). NaH (60%, 12 mg, 0.30 mmol) was added and the reaction mixture was stirred for 10 minutes. The mixture was filtered and was purified by reverse phase preparative liquid chromatography utilizing a gradient of 10-99% acetonitrile in water containing 5 mM hydrochloric acid to give (4-methoxy-3-(methylsulfonyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 452.1, found 453.5 (M+1)+; Retention time: 1.78 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.87 (d, J=2.0 Hz, 1H), 7.86-7.81 (m, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.22-7.02 (m, 3H), 6.28 (t, J=3.1 Hz, 1H), 6.16 (d, J=2.3 Hz, 1H), 4.52-4.18 (m, 1H), 4.00 (s, 3H), 3.58 (s, 3H), 3.28 (s, 3H), 1.98 (s, 4H).