Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B-].[Na+].[CH2:3]1[O:13][C:6]2([CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)[O:5][CH2:4]1.Cl>CO>[CH2:4]1[O:5][C:6]2([CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2)[O:13][CH2:3]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [B-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
Sodium borohydrate (2.4 g, 64 mmol) was added in portions to a stirred ice cold solution of 1,4 cyclohexanedione monoethylene ketal 38 (20 g, 128 mmol) in 60 mL of methanol (Step 35). After addition was complete, 1N HCl was added to the solution dropwise until a pH of 8 was obtained and then the solvent was removed by roto-evaporation. The product 39 (16.8 g, 84%) showed a single spot on TLC (Rf=0.4, ethyl acetate/hexane 20:80 solvent system, visualization was with acidic vanillin ethanol solution) and was used without further purification. 1H NMR (CDCl3) δ 1.6-1.9 (m, 8H, ring-CH2), 3.8 (m, 1H, CH-O), 4.0 (s, 4H, ketal-CH2), 5.3 (s, 1H, OH).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[C:5]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:22].[CH3:23][C:24]1([CH3:27])[CH2:26][O:25]1>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[C:5]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:23][C:24]([OH:25])([CH3:27])[CH3:26])[CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:22]
Reactant: Cc1cn2c(N)c(Cl)cc(C(=O)NCC3CCNCC3)c2n1
Reactant: CC1(C)CO1
Product: Cc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CC(C)(C)O)CC3)c2n1

Procedure:
The title compound was prepared according to the procedure described in Example 14 from 5-amino-6-chloro-2-methyl-N-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridine-8-carboxamide (Example 15, Step 2) and 2,2-dimethyloxirane.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:38])[NH:21][C:9]4[CH:10]=[C:11]([C:19]#[N:20])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[O:36][N:35]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C#N)NC(=O)CC(c1cccc(-c3cc(C)no3)c1)=N2

Procedure:
The title compound was prepared from [4-cyano-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example M93) (0.36 g, 0.68 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (94 mg, 34%).
Reaction SMILES: [F:1][C:2]([F:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][O:4][CH2:5][CH:6]=[CH2:7].C1(CCCC[O:25]CCCO)C=CC=CC=1>>[F:1][C:2]([F:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][O:4][CH2:5][CH2:6][CH2:7][OH:25]
Reactant: OCCCOCCCCc1ccccc1
Reactant: C=CCOCC(F)(F)c1ccccc1
Product: OCCCOCC(F)(F)c1ccccc1
Yield: 96 %

Procedure:
Obtained from Intermediate 80 (10.6 g, 53 mmol) by the procedure described in Intermediate 12. Purification by column chromatography with silica gel eluting with ethyl acetate/n-hexane (from 1:4 to pute ethyl acetate) gave the title compound (10.7 g, 96%) as oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:45]([O:51][CH2:52]I)(=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30][CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH2:52][O:51][C:45](=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (4.1 g) in N,N-dimethylformamide (41 ml) was added iodomethyl pivalate (1.55 g) at 0° C., and the mixture was stirred for 15 minutes at same temperature. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (200 ml). The extract was washed with a saturated aqueous sodium bicarbonate and water, followed by drying over magnesium sulfate. The solution was evaporated in vacuo to give pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.75 g).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].CO.[CH3:17]CN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:17])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCc1n[nH]c2cc(C(=O)O)ccc12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCc1n[nH]c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 1.35 g (7.1 mmol) of 3-ethyl-1H-indazol-6-yl-carboxylic acid, [Marfat, A., et al., U.S. Pat. No. 6,262,040], 2.9 mL (71 mmol) of methanol, and 0.95 g (7.8 mmol) of DMAP in 60 mL of CH2Cl2 was added 1.5 g (7.8 mmol) of EDCI-HCl. This mixture was stirred at room temperature overnight, concentrated and the residue dissolved in 50 mL of ethyl acetate. The organic layer was successively washed with 40 mL of 1N HCl, 40 mL of water and 40 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography over silica gel using a gradient of 35% to 50% ethyl acetate in hexanes over 20 minutes as eluant to yield 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. 1H NMR (CDCl3) δ 11.7 (s, 1H), 8.18 (s, 1H), 7.73 (apparent q, 9.0 Hz, 2H), 3.94 (s. 3H), 3.03 (q, 7.5 Hz, 2H), 1.42 (t, 7.5 Hz, 3H).
Reaction SMILES: C([Li])CCC.[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:12][Si:13]([CH3:23])([CH:21]=[CH2:22])[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.O>C1COCC1>[CH3:12][Si:13]([CH3:23])([CH2:21][CH2:22][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1
Reactant: C=C[Si](C)(C)c1ccc(N)cc1
Reactant: C1CCNCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(CCN1CCCCC1)c1ccc(N)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
At 50° C., n-butyl lithium (8 ml/L, 21 ml) was slowly added dropwise into the THF solution of piperidine (3.5 g, 41 mmol). After the solution was stirred at 50° C. for 30 minutes, compound 6c (0.6 g, 3.4 mmol) in THF was slowly added into the reaction mixture. After the reaction mixture was stirred at 50° C. for 2 hours, three times of water was added into the reaction solution, followed by extracted with ethyl acetate. The organic layer was dried and evaporated to give a crude product, which was purified using column chromatography to give the product.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]>CN(C=O)C>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCC(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 14 h
Yield: 101.1 %

Procedure:
A mixture of sodium hydride (60% in mineral oil, 2.4 g, 60.5 mmol, 1.1 eq) and diethyl malonate (8.34 mL, 55 mmol, 1 eq) in DMF (200 mL) was cooled to 0° C. and 5-bromo-1-pentene (6.5 mL, 55 mmol, 1 eq) was added dropwise. The reaction mixture was warmed to rt, stirred for 14 hours and then partitioned between ether and water. The layers were separated, the aqueous layer was extracted with ether (2×250 mL) and the combined organic phases were washed with water (2×) and brine, dried over MgSO4 and concentrated to give E1.1 as a colorless oil (12.7 g, 100% yield). 1H NMR (400 MHz, CDCl3): δ 5.71 (m, 1H), 4.92 (m, 2H), 4.12 (q, J=7.1 Hz, 4H), 3.25 (t, J=7.58 Hz, 1H), 2.01 (m, 2H), 1.83 (m, 2H), 1.36 (m, 2H), 1.20 (t, J=7.1 Hz, 6H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(O[C:32]1(O[Si](C)(C)C)[CH2:34][CH2:33]1)C.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:32]1([N:21]2[CH2:22][C:19]([CH2:23][C:24]#[N:25])([N:17]3[CH:18]=[C:14]([C:12]4[N:11]5[CH:26]=[CH:27][N:28]=[C:10]5[CH:9]=[C:8]([C:6]5[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=5)[N:13]=4)[CH:15]=[N:16]3)[CH2:20]2)[CH2:34][CH2:33]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C5CC5)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
To a fine suspension of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62, 50.2 mg, 0.107 mmol) in 2:1 MeOH/acetic acid (0.60 mL) was added (1-ethoxycyclopropoxy)trimethylsilane (94.2 mg, 0.535 mmol) and the mixture was stirred at ambient temperature for 5 minutes. Sodium cyanoborohydride (42.5 mg, 0.642 mmol) was added in one portion and the mixture was stirred at 50° C. for 3 hours. The mixture was cooled to ambient temperature and concentrated to dryness. The residual white solid was partitioned into DCM and 1M K2CO3 (3 mL each) and the mixture was stirred until both layers were homogeneous. The DCM layer was removed and the aqueous layer was extracted with DCM. The combined DCM extracts were dried over Na2SO4, filtered through a Celite pad and concentrated to give a colorless glass. The glass was purified on a silica gel column eluting with a step gradient of EtOAc, 5% MeOH/EtOAc, and 10% MeOH/EtOAc to furnish the title compound (35 mg, 82% yield) as a white solid. MS (apci) m/z=400.2 (M+H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[C:31]([CH3:37])=[N:30][C:29]([OH:38])=[CH:28]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[OH:38][C:29]1[N:30]=[C:31]([CH3:37])[C:32]2[C:27]([C:28]=1[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]3[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)=[CH:26][C:25]([O:24][CH3:23])=[C:34]([O:35][CH3:36])[CH:33]=2
Reactant: COc1ccc2nc(NCCNC(C)=O)c(CCl)cc2c1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2nc(NCCNC(C)=O)c(Cc3c(O)nc(C)c4cc(OC)c(OC)cc34)cc2c1
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(2-(3-(chloromethyl)-6-methoxyquinolin-2-ylamino)ethyl)acetamide hydrochloride SLA 41176 (115 mg, 0.33 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH18060 (73 mg, 0.33 mmol) followed by a 2 N aq. LiOH solution (0.33 mL, 0.66 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 90:10) provided N-(2-(3-((3-hydroxy-6,7-dimethoxy-1-methylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ylamino)ethyl)acetamide. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of 0.49 M HCl in MeOH (2 mL) and the solution was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afforded N-(2-(3-((3-hydroxy-6,7-dimethoxy-1-methylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ylamino)ethyl)acetamide dihydrochloride 73 as a yellow solid (19.5 mg, 10% yield).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.[C:7]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([C@@H:27]3[C:35]4[C:30](=[C:31](Br)[CH:32]=[C:33]([F:36])[CH:34]=4)[CH2:29][C@H:28]3[OH:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[C:12]=2[CH2:11]1)(=[O:9])[CH3:8].C([O-])([O-])=O.[K+].[K+]>CC#N.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:7]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([C@@H:27]3[C:35]4[C:30](=[C:31]([CH:1]5[CH2:3][CH2:2]5)[CH:32]=[C:33]([F:36])[CH:34]=4)[CH2:29][C@H:28]3[OH:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[C:12]=2[CH2:11]1)(=[O:9])[CH3:8]
Reactant: OB(O)C1CC1
Reactant: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(Br)c3C[C@H]2O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(C4CC4)c3C[C@H]2O)C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
According to Scheme 14: A mixture of cyclopropylboronic acid (28 mg, 0.33 mmol), 3-[5-acetyl-1-((1R,2R)-4-bromo-6-fluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (11d) (0.05 g, 0.10 mmol), K2CO3 (83 mg, 0.606 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.005, 0.015 mmol) in CH3CN (2 ml) and water (0.75 ml) was stirred at 110° C. for 2 h under microwave irradiation. The mixture was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 9 mg of 3-[5-acetyl-1-((1R,2R)-4-cyclopropyl-6-fluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (20a).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1)=[O:16].[CH:23](=[O:25])[CH3:24]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:23]([OH:25])[CH3:24])[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1)=[O:16]
Reactant: COC(=O)C1CCSCC1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C(C)O)CCSCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of N,N-diisopropylamine (1.51 g, 2.1 mL, 15 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at −78° C. under nitrogen. n-Butyl lithium (6 mL, 15 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min. A solution of tetrahydro-thiopyran-4-carboxylic acid methyl ester (1.60 g, 10 mmol) in tetrahydrofuran (4 mL) was added and the reaction mixture was stirred at −78° C. for 20 min. Acetaldehyde (1.32 g, 1.7 mL, 30 mmol) was then added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and ice-cold hydrochloric acid (2 M) was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the aqueous phase and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 3:1 to 1:3 to afford the title compound (1.77 g, 87%) as a yellow oil. 1H NMR (300 MHz, d6-DMSO): δ 0.96 (d, J=6.5 Hz, 3H), 1.46-1.73 (m, 2H), 2.12-2.28 (m, 2H), 2.43-2.57 (m, 4H), 3.50-3.58 (m, 1H), 3.63 (s, 3H), 4.85 (d, J=5.8 Hz, 1H). LCMS (m/z) 227.1 [M+Na], Tr=1.53 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1)(=[O:22])=[O:21]
Reactant: CCc1ccc(CCO)nc1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1ccc(CCOS(C)(=O)=O)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
66.0 g (436 mmol) of 2-(5-ethylpyridin-2-yl)ethanol was dissolved in 500 mL of toluene. 72.5 mL (523 mmol) of triethylamine was added to this solution, at room temperature. The resulting solution was cooled between 0 and 10° C., after which 34.0 mL (438 mmol) of methanesulphonyl chloride was added dropwise during 75 minutes. When addition was completed, it was stirred for 1 hour at room temperature. Next, the organic phase was washed with a saturated solution of sodium bicarbonate (400 mL) and with water (400 mL), and was dried over sodium sulphate, obtaining a toluene solution of 2-(5-ethylpyridin-2-yl)ethyl methanesulphonate, a compound of formula (III) in which Z=OMs.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]1([C:36]2[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:35]=[CH:34][C:33]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:32][CH:31]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(-c4ccccc4)cc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-phenylphenol: ESMS m/e: 611.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH3:17])=[C:12]([CH:18]2[CH2:20][O:19]2)[C:11]=1[O:21][CH3:22])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(O)C.[CH3:27][CH:28]([NH2:30])[CH3:29].CCN(C(C)C)C(C)C>>[Cl:16][C:14]1[C:13]([CH3:17])=[C:12]([CH:18]([OH:19])[CH2:20][NH:30][CH:28]([CH3:29])[CH3:27])[C:11]([O:21][CH3:22])=[C:10]([CH:8]([NH:7][C:6](=[O:23])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:9])[CH:15]=1
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CO1
Reactant: CC(C)N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C(O)CNC(C)C
Temperature: 80 °C
Yield: 4.9 %

Procedure:
tert-Butyl[1-(5-chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl]carbamate (100 mg, 0.29 mmol, from Example 190, Step 1) was stirred in ethanol (2.0 mL, 34 mmol), 2-propanamine (120 μL, 1.5 mmol) and DIPEA (260 μL, 1.5 mmol) was added. The mixture was stirred at 80° C. over the weekend. Purification by preparative LC/MS (pH 10) gave the desired compound (5.7 mg, 5%). LCMS calculated for C20H34ClN2O4 (M+H)+: m/z=401.2. found: 401.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[O:1]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccnc(CO)c1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(COc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Methyl 2-(hydroxymethyl)isonicotinate (2.232 g, 13.35 mmol) dissolved in THF (15 mL) and phenol (1.426 mL, 16.02 mmol) and triphenylphosphine (3.71 mL, 16.02 mmol) were added. The mixture was cooled to 0° C. (E)-diisopropyl diazene-1,2-dicarboxylate (3.24 g, 16.02 mmol) was added dropwise, the ice-bath removed and the reaction stirred at room temperature for 2 h. The solvent was evaporated and the residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. 4:1 of EtOAc in heptane over 10 CV was used as mobile phase. Methyl 2-(phenoxymethyl)isonicotinate (2.65 g, 82%) was isolated. 1H NMR (400 MHz, cdcl3) δ 3.96 (s, 3H), 5.26 (s, 2H), 6.95-7.04 (m, 3H), 7.27-7.34 (m, 2H), 7.76-7.80 (m, 1H), 8.10 (s, 1H), 8.75 (d, 1H). MS m/z 244 (M+H)+
Reaction SMILES: [F:1][C@:2]([CH3:29])([C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2)=[O:7])[C:3]([OH:5])=O.[F:30][C:31]([F:38])([C:34]([F:37])([F:36])[F:35])[CH2:32][NH2:33]>>[F:1][C@@:2]([CH3:29])([C:3]([NH:33][CH2:32][C:31]([F:38])([F:30])[C:34]([F:37])([F:36])[F:35])=[O:5])[C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2)=[O:7]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: COCCN1C(=O)[C@@H](NC(=O)[C@@](C)(F)C(=O)O)c2ccccc2-c2ccccc21
Product: COCCN1C(=O)[C@@H](NC(=O)[C@@](C)(F)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using (R)-2-fluoro-N—[(S)-5-(2-methoxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-methyl-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. White solid (69%). MS: m/e=532(M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[Cl:16]N1C(=O)CCC1=O.CN(C)C=O>O>[NH2:1][C:2]1[C:3]([Cl:16])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(Cl)c(N)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A mixture of ethyl 7-amino-1H-indole-2-carboxylate (2.30 g), N-chlorosuccinimide (1.40 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature overnight. To the reaction mixture was added water, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.59 g, yield 63%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 217-218° C. (decomposition).