Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)=[CH:25][CH:24]=1)=[O:21].C(NC(C)C)(C)C>CN(C)C=O>[F:38][C:36]([F:37])([F:39])[C:33]1[CH:34]=[CH:35][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:20]([N:16]3[CH2:15][CH2:14][CH:13]([N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:6][C:7]4[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=4)[CH2:18][CH2:17]3)=[O:21])=[CH:24][CH:25]=2)=[N:31][CH:32]=1
Reactant: c1cncc(CN(CC2CC2)C2CCNCC2)c1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N(Cc2cccnc2)CC2CC2)CC1

Procedure:
The title product was prepared from cyclopropylmethyl-piperidin-4-yl-pyridin-3-ylmethylamine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (47%, off-white solid. HPLC-MS m/z=(M+1) 513.3, Rt: 2.70 min.
Reaction SMILES: C(OC(=O)NN=CC1N=C(C(C)(C)C)NC=1C)C.C([O:21][C:22](=O)[NH:23][N:24]=[CH:25][C:26]1[N:27]=[C:28]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:29][C:30]=1[CH:31]([CH3:33])[CH3:32])C>>[CH2:34]([C:28]1[N:27]2[C:22](=[O:21])[NH:23][N:24]=[CH:25][C:26]2=[C:30]([CH:31]([CH3:33])[CH3:32])[N:29]=1)[CH:35]([CH3:37])[CH3:36]
Reactant: CCOC(=O)NN=Cc1nc(CC(C)C)[nH]c1C(C)C
Agent: CCOC(=O)NN=Cc1nc(C(C)(C)C)[nH]c1C
Product: CC(C)Cc1nc(C(C)C)c2cn[nH]c(=O)n12

Procedure:
The general procedure of Example 81 is repeated but replacing the 3-[(2-tert-butyl-5-methyl-4-imidazolyl)-methylene]carbazic acid ethyl ester employed in that example with 3-[(2-isobutyl-5-isopropyl-4-imidazolyl)methylene]carbazic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][CH2:26][CH2:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][CH2:27][CH2:26][O:25][CH:20]4[CH2:21][CH2:22][CH2:23][CH2:24][O:19]4)=[CH:30][CH:31]=3)=[O:18])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1ccc(OCCOC2CCCCO2)cc1
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(OCCOC3CCCCO3)cc2)nnn1Cc1ccc(Cl)c(Cl)c1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Intermediate 11) (0.3 g, 1 mmol), 4-{[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]oxy}aniline (Intermediate 18) (0.28 g, 1.2 eq), HATU (0.8 g, 2 eq), and NEt3 (440 μL, 3 eq) in DMF was stirred at 45° C. for 18 hours. The solvent was evaporated and the residue was washed with water and extracted with a mixture of ether and ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The title compound was obtained and used in the next step without purification and isolation.
Reaction SMILES: [NH3:1].CO.[CH:4]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[C:14]([CH:18]=O)[NH:15]3)=[CH:11][CH:10]=2)[CH2:6][CH2:5]1>[Ni]>[CH:4]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[C:14]([CH2:18][NH2:1])[NH:15]3)=[CH:11][CH:10]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1cc2ccc(OCC3CC3)cc2[nH]1
Reactant: N
Agent: [Ni]
Solvent: CO
Product: NCc1cc2ccc(OCC3CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To an ammonia-methanol (5 mL) solution of 6-cyclopropylmethoxy-1H-indole-2-carbaldehyde (144 mg, 669 μmol) described in Production Example 73-1-4 was added Raney nickel, which was stirred at room temperature for 8 hours under hydrogen atmosphere. The reaction mixture was filtered through Celite and the filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (91 mg, 63%) as a pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1nsc(NC(=O)OC(C)(C)C)n1
Reactant: CCCCCCC=O
Product: CCCCCCC(O)C(C(=O)OCC)c1nsc(NC(=O)OC(C)(C)C)n1

Procedure:
1.0 g (3.5 mMol) of product from Example 28 were reacted with 1.46 ml (~10 mMol) of n-heptanal in the manner described in Example 29. Yield of erythro/threo mixture of the title compound: 1.4 g.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[N:9]2[C:10]3[C:15]([C:16]([OH:18])=[CH:17][C:8]2=[N:7][N:6]=1)=[CH:14][CH:13]=[CH:12][N:11]=3.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[N+:1]([C:17]1[C:8]2[N:9]([N:5]=[N:6][N:7]=2)[C:10]2[C:15]([C:16]=1[OH:18])=[CH:14][CH:13]=[CH:12][N:11]=2)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc2nnnn2c2ncccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)c2cccnc2n2nnnc12
Temperature: 25 °C

Procedure:
Nitric acid (1.33 mL of 16M) was added to a suspension of tetrazolo[1,5-a][1,8]naphthyridin-5-ol (4 g, 21 mmole) in acetic acid (50 mL). The reaction mixture was heated on a steam bath for 5 minutes then cooled to ambient temperature. Sodium acetate (0.3 eq) in a small amount of water was added to the reaction mixture. The resulting solid was isolated by filtration and dried to provide 5 g of 4-nitrotetrazolo[1,5-a][1,8]naphthryidin-5-ol as a solid, m.p. 278° C. (decomposition). Analysis: Calculated for C8H4N6O3+1.1 H2O: %C, 38.12; %H, 2.48; %N, 33.35; Found: %C, 37.99; %H, 2.41; %N, 32.82.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[C:26]1([CH3:34])[CH:31]=[CH:30][C:29]([NH:32]N)=[CH:28][CH:27]=1>>[C:26]1([CH3:34])[CH:31]=[CH:30][C:29]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: Cc1ccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and p-tolyl-hydrazine according to example 43 gave the desired product. MS: M=413.3 (M+H)+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[CH:9]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1.[NH4+].[Cl-].C(Cl)Cl>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: N#CC1CCC1
Reactant: Fc1ccc(I)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#CC1(c2ccc(I)cn2)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
In a dry flask under argon, 2-fluoro-5-iodo-pyridine (3.85 g, 17.3 mmol) and cyclobutanecarbonitrile (1.40 g, 17 mmol) were dissolved in dry toluene (15 mL). The solution was cooled to 0° C. and sodium bis(trimethylsilyl)amide (1.0 M, 19 mL, 19 mmol) was added dropwise over 15 min. After 1 h, the solution was allowed to warm to room temperature and stirred for 26 h. The reaction was diluted with saturated aqueous NH4Cl (10 mL) and CH2Cl2 (10 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to yield 4.0 g of 1-(5-iodo-pyridin-2-yl)-cyclobutane carbonitrile as a viscous, light brown oil, m/z 285.4 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(=O)(O)[O-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O.CC(C)=O>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-2-methylpiperazine (13.85 g, 138 mmol) and sodium bicarbonate (52.3 g, 622 mmol) were partially dissolved in a mixture of water (182 ml) and acetone (112 ml). A solution of benzoyl chloride (17.7 ml, 152 mmol) in acetone (56 ml) was added dropwise over 1 hour with vigorous stirring. After stirring for 16 hours at RT, the acetone was stripped on the rotovap, water (400 ml) was added, and the solution acidified (6M HCl) to a pH less than 2. The aqueous phase was washed three times with dichloromethane (200 ml) and then 5M sodium hydroxide was added to bring pH over 12. The resulting solution was extracted three times with dichloromethane (200 ml), dried (MgSO4) and evaporated to give (R)-(3-methylpiperazin-1-yl)(phenyl)methanone 62 as a yellow oil, 15.1 g (54% of theoretical). LC/MS m/z=205 (M+H+).
Reaction SMILES: Cl.Cl.C(N1CCC(N(C)C)CC1)C1C=CC=CC=1.Cl.Cl.[CH3:21][N:22]([CH3:29])[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.F[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=1[N+:41]([O-:43])=[O:42].C(N(CC)CC)C>[Pd].O.C1COCC1.CO>[CH3:21][N:22]([CH3:29])[CH:23]1[CH2:28][CH2:27][N:26]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][C:32]=2[N+:41]([O-:43])=[O:42])[CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CN(C)C1CCNCC1
Agent: [Pd]
Agent: CN(C)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C1CCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 1-benzyl-N,N-dimethylpiperidin-4-amine dihydrochloride (6.7 g, 23 mmol) was added Pd/C (10%, 2.4 g) under argon. Methanol (100 ml) was added via syringe, and H2 gas was introduced and the mixture stirred vigorously under an atmosphere of H2. After 48 h, the mixture was flushed with nitrogen, filtered through celite and concentrated to afford a mixture of starting material and N,N-dimethylpiperidin-4-amine dihydrochloride as a white solid. This solid was treated with 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (3.2 ml, 22.9 mmol), triethylamine (12.7 ml, 92 mmol), and 50 ml dry THF. The mixture was heated to 75° C. with a water-cooled reflux condenser for 12 h. The mixture was allowed to cool to ambient temperature, was filtered through a fritted funnel, and concentrated to an orange oil. The residue was purified by silica gel chromatography (MC/MeOH/conc. NH4OH) to give the desired product as an orange oil. MS (m/z): 318.1 (M+H)+. Calc'd for C14H18F3N3O2: 317.31.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[CH2:19][NH:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24].C(N(CC)CC)C.[Cl:33][C:34]1[C:42]([O:43][CH2:44][CH2:45][Br:46])=[C:41]([O:47][CH3:48])[CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37].[OH-].[Na+]>ClCCl>[Cl:33][C:34]1[C:42]([O:43][CH2:44][CH2:45][Br:46])=[C:41]([O:47][CH3:48])[CH:40]=[CH:39][C:35]=1[C:36]([N:20]([CH2:19][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[C:10]=1[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:37]
Reactant: COc1ccccc1Cc1c(CNCCC(C)C)nc2ccccn12
Reactant: COc1ccc(C(=O)Cl)c(Cl)c1OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OCCBr)c2Cl)nc2ccccn12
Temperature: 25 °C
Reaction time: 65 h
Yield: 64.4 %

Procedure:
To a solution of ({3-[(2-methoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl) (3-methylbutyl) amine (1.4 g, 4.2 mmol) in dichloromethane (15 ml) is added triethylamine (0.7 ml, 5 mmol) followed by 2-chloro-3-bromoethoxy-4-methoxybenzoic acid chloride (1.5 g, 4.5 mmol). The reaction mixture is stirred at ambient temperature for 65 h. Aqueous 1 N sodium hydroxide (20 ml) is added and the resulting mixture is extracted with dichloromethane (3×20 ml). The combined organic layers are dried over magnesium sulfate, filtered, and evaporated at reduced pressure. Chromatography on silica gel with ethyl acetate provides 1.7 g (65%)of (2-chloro-3-bromoethoxy-4-methoxyphenyl)-N-({3-[(2-methoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)} methyl)-N-(3- methylbutyl)carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[N:9]([C:18]1[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][C:19]=1O)[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]>C1COCC1>[O:24]=[C:23]1[C:18]2[N:9]([C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=3)[C:13]#[N:14])[C:3]3[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=3[NH:1][C:19]=2[CH2:20][CH2:21][CH2:22]1
Reactant: N#Cc1cccc(N(C2=C(N)CCCC2=O)C2=C(O)CCCC2=O)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(N2C3=C(CCCC3=O)NC3=C2C(=O)CCC3)c1

Procedure:
3-[(2-Amino-6-oxo-cyclohex-1-enyl)-(2-hydroxy-6-oxo-cyclohex-1-enyl)-amino]-benzonitrile (0.4 mmoL) in THF (5 mL) was treated with NaNH2 (1 mmoL) at 70° C. for 6 h. The solvent was removed and the residue was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, which was then purified by silica gel column chromatography to give the title compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:37]1[CH:36]=[CH:35][C:34]([C:30]2[CH:29]=[C:28]([C:27]3[CH2:26][C:25](=[O:41])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:23])([F:21])[F:22])[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccncc3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M33) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (175 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C@H:8]([CH2:17][C@@H:18]([OH:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:9][C:10](OC(C)(C)C)=[O:11].O.[OH-].[Na+]>C1COCC1>[F:7][C@H:8]([CH2:17][C@@H:18]([OH:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:9][CH2:10][OH:11]
Reactant: CCCC[C@H](O)C[C@@H](F)CC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](O)C[C@@H](F)CCO
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In a 100 ml flask were charged dried THF and 0.59 g of lithium aluminum hydride in a nitrogen stream, followed by cooling to 5° C. To the mixture was added dropwise a solution of 5.0 g of the compound obtained in Step 5 in 17 ml of dried THF over 20 minutes, followed by allowing the mixture to react at 35 to 40° C. for 3 hours. The reaction mixture was again cooled to 5° C., and a solution of 0.6 g of water and 2 ml of THF was added thereto over 30 minutes. Then, 1.6 ml of a 4% sodium hydroxide aqueous solution was added thereto, followed by stirring at that temperature for 1 hour.
Reaction SMILES: [NH:1]1[C@@H:6]2[CH2:7][CH2:8][CH2:9][C@@H:5]2[CH2:4][O:3][C:2]1=[O:10].F[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][N:13]=1.[H-].[Na+]>CN(C=O)C>[C:20]1([C:19]#[C:18][C:15]2[CH:16]=[CH:17][C:12]([N:1]3[C@@H:6]4[CH2:7][CH2:8][CH2:9][C@@H:5]4[CH2:4][O:3][C:2]3=[O:10])=[N:13][CH:14]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Fc1ccc(C#Cc2ccccc2)cn1
Reactant: O=C1N[C@@H]2CCC[C@@H]2CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OC[C@H]2CCC[C@H]2N1c1ccc(C#Cc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
In a 10 ml Round bottomed flask were dissolved (4aS,7aR)-hexahydro-cyclopenta[d]-[1,3]oxazin-2-one (80 mg, 0.57 mmol, 1.0 equiv.) and 2-fluoro-5-(phenylethynyl)pyridine (112 mg, 0.57 mmol, 1.0 equiv.) in 2 ml of DMF. Sodium hydride (60% suspension) (29.5 mg, 0.74 mmol, 1.3 equiv.) were added and the brown suspension was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The combined organic phases were dried, filtered and concentrated. The crude material was purified by flash chromatography over a prepacked silica column eluting with 0-50% ethyl acetate in heptane gradient to yield 42.5 mg of the title compound as colorless amorphous solid, MS: m/e=319.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:14])[C:5]2[CH:15]=[CH:16][C:17]([N+:19]([O-])=O)=[CH:18][C:4]=2[O:3]1.[Cl-].[NH4+].CO>[Zn].O>[NH2:19][C:17]1[CH:16]=[CH:15][C:5]2[N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:14])[CH2:7][C:2]([CH3:22])([CH3:1])[O:3][C:4]=2[CH:18]=1
Reactant: CC1(C)CN(c2cccc[n+]2[O-])c2ccc([N+](=O)[O-])cc2O1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CC1(C)CN(c2cccc[n+]2[O-])c2ccc(N)cc2O1
Temperature: 5 °C
Reaction time: 14 h
Yield: 101 %

Procedure:
To a mixture of 8.05 g 2-(3,4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-4-yl)pyridine N-oxide, 28.50 g ammonium chloride, 140 ml methanol and 140 ml water, was added 34.94 g zinc powder under ice cooling, and the resulting mixture was stirred at 5° C. for 14 hours. The insoluble matters were filtered off from the reaction mixture, the filtrate was concentrated, the concentrate was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and the solvents were distilled off form the dried solution, giving 7.32 g of crude 2-(7-amino-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-4-yl)pyridine N-oxide.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]3[C:26]4[CH:27]=[CH:28][N:29]=[CH:30][C:31]=4[CH:32]=[CH:33][CH:34]=3)(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.O.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.C(OCC)(=O)C>[NH2:8][C@H:12]([CH2:11][OH:10])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]2[C:26]3[CH:27]=[CH:28][N:29]=[CH:30][C:31]=3[CH:32]=[CH:33][CH:34]=2)(=[O:24])=[O:23])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NS(=O)(=O)c3cccc4cnccc34)cc2)COC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CO)CCc1ccc(NS(=O)(=O)c2cccc3cnccc23)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
(S)-4-{2-[4-(isoquinoline-5-sulfonylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (155 mg) was dissolved in acetonitrile (1.5 ml) and water (3 ml) before addition of trifluoroacetic acid (68.6 μl) at room temperature. The reaction mixture was then warmed to 50° C. and stirred for 5 hours and then cooled at room temperature and stirred for 12 hours. Ethyl acetate (4 ml) was added and then the solution basified by addition of 1N aqueous solution of sodium hydroxide until pH 14 followed by stirring for 15 minutes. The two layers were then separated and the aqueous was extracted twice with ethyl acetate, the combined organic layers were dried over Mg2SO4, filtered and concentrated in vacuo to give isoquinoline-5-sulfonic acid [4-((S)-3-amino-4-hydroxy-butyl)-phenyl]-amide (109 mg) as a yellow solid. MS (ISP): 372.2 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][CH3:10])[CH:7]=1.CC1CCCO1.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li]CCCC.Cl>C1(C)C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([B:17]([OH:22])[OH:18])[CH:3]=[N:4][CH:5]=1)#[C:9][CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC#Cc1cncc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CC1CCCO1
Product: CC#Cc1cncc(B(O)O)c1
Temperature: -50 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
3-Bromo-5-(prop-1-ynyl)pyridine (Intermediate 14, 25 g, 117 mmol), 2-methyl-tetrahydrofuran (60 mL), toluene (200 mL) and triisopropyl borate (33.2 mL, 140.78 mmol) were mixed. The mixture was cooled to −50° C. To the cold mixture was added n-BuLi (59.8 mL, 149.5 mmol) dropwise during 30 min. The mixture was stirred for 60 min. at −50° C. 2 M HCl aq. (100 mL) was added. The mixture was then allowed to reach r.t. and stirred for 20 min. The organic and water phase were separated. The organic phase was extracted with NaOH (2 M aq.) (2×100 mL). The water phases were combined and the pH was adjusted to pH 5. The product was extracted with 2-methyl-THF (2×100 mL). The organic phase was dried with Na2SO4, filtered and concentrated to give the title compound (16.47 g, 87% yield): 1H NMR (500 MHz, CD3OD) δ ppm 2.11 (s, 3H) 8.21 (br. s., 1H) 8.53 (m, 2H); MS (APCI+) m/z 162.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:30][C:26]2([CH3:25])[CH2:29][O:28][CH2:27]2)=[O:21])=[CH:17][N:16]=1
Reactant: CC1(N)COC1
Reactant: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)NC2(C)COC2)cn1
Yield: 61 %

Procedure:
As described for example 19b, 6-((4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (98 mg, 0.3 mmol) was converted, using 3-methyl-3-oxetanamine instead of 4-aminotetrahydropyran, to the title compound (72 mg, 61%) which was obtained as a white solid. MS: m/e=398.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:15](=[N:16][CH:17]=1)[NH:14][CH2:13][CH2:12][CH2:11]2.[C:18]([N:26]=C=O)(=[O:25])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:15](=[N:16][CH:17]=1)[N:14]([C:18]([NH2:26])=[O:25])[CH2:13][CH2:12][CH2:11]2
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1ccncc1-c1cnc2c(c1)CCCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccncc1-c1cnc2c(c1)CCCN2C(N)=O
Temperature: 25 °C
Yield: 23.7 %

Procedure:
To the solution of 6-(4-Methyl-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (50 mg, 0.22 mmol) in 5.0 mL of anhydrous DCM is added benzoyl isocyanate (39 mg, 0.24 mmol) and the solution is heated to reflux for 3 hrs. Then the solvent is removed in vacuo and to the residue is added 5.0 mL of EtOH. Then K2CO3 (61 mg, 44 mmol) is added and the mixture is heated to reflux for 5 hrs. After cooling down to room temperature, the solid is filtered off. The filtrate is evaporated to dryness. The residue is dissolved in DCM, washed with water and brine. The organic layer is separated, dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative HPLC to give 14 mg of the titled product.