Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]([CH3:18])[C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.Cl.[C-:20]#[N:21].[K+]>CO.O>[CH3:3][N:4]([CH3:18])[C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][C:8]([NH:21][CH3:20])([C:1]#[N:2])[CH2:7][CH2:6]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: CN
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNC1(C#N)CCC(c2ccccc2)(N(C)C)CC1
Temperature: 0 °C
Reaction time: 120 h

Procedure:
40% aqueous methylamine solution (8.7 mL, 69 mmol) and 4-dimethylamino-4-phenylcyclohexanone (3.13 g, 14.4 mmol) dissolved in methanol (15 mL) were added to a solution of 4N hydrochloric acid (3.75 mL) and methanol (2.25 mL) cooled to 0° C. The reaction mixture was then mixed with potassium cyanide (2.25 g, 34 mmol) and stirred for 5 d at RT. For work up the mixture was mixed with water (60 mL) and extracted with ether (3×50 ml). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][O:25][CH3:26])[C:13]([C:27]#[N:28])=[CH:12]2)=[CH:7][C:6]=1[OH:29])C.C(O)C.[OH-].[Li+].Cl>O.O1CCCC1>[C:27]([C:13]1[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:15][N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[C:6]([OH:29])[CH:7]=2)[CH:12]=1)#[N:28]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3OCCOC)c2)cc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1ccccc1-c1cn(-c2ccc(C(=O)O)c(O)c2)cc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.1 %

Procedure:
To a solution of 4-{3-cyano-4-[2-(2-methoxyethoxy)phenyl]pyrrole-1-yl}-2-hydroxy benzoic acid ethyl ester (0.072 g) in a mixed solvent of ethanol (9 mL) and tetrahydrofuran (3 mL) was added 1 mol/mL aqueous lithium hydroxide solution (2.7 mL), and this mixture was stirred at room temperature for 48 hours. This reaction mixture was poured into 1 mol/L hydrochloric acid (2.7 mL), and to this mixture was added water (30 mL). The precipitated solid was collected by filtration. This obtained solid was washed with water, dried under reduced pressure at 50° C. to give the title compound (0.051 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[N:18]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2>>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[N:18]1)[N:5]=[CH:4][CH:3]=[C:2]2[NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2)#[N:13]
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCn1ccnn1
Reactant: Nc1ccc2[nH]ccc2c1
Product: N#Cc1cc2c(Nc3ccc4[nH]ccc4c3)ccnc2cc1OCCn1ccnn1
Yield: 93.6 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6-cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinoline (60 mg, 0.2 mmol) was reacted with 5-aminoindole (32 mg, 0.25 mmol) to give 6-cyano-4-(indol-5-ylamino)-7-(2-(1,2,3-triazol-1-yl)ethoxy)quinoline (74 mg, 86%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N+:11]([C:14]1[CH:31]=[CH:30][C:17]([CH2:18][O:19][C:20]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][OH:29])[CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(N(CC)CC)C>ClCCl>[N+:11]([C:14]1[CH:31]=[CH:30][C:17]([CH2:18][O:19][C:20]([N:22]2[CH2:27][CH2:26][CH:25]([CH:28]=[O:29])[CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (2 ml) in dry dichloromethane (50 ml) was added dropwise dry dimethyl sulfoxide (3.4 ml) at -60° C. and the resulting mixture was stirred for 10 minutes. To the mixture was added a solution of N-p-nitrobenzyloxycarbonyl-4-hydroxymethylpiperidine (5.88 g) in dry dichloromethane (40 ml) at the same temperature. After stirring for 15 minutes, triethylamine (14 ml) was added to the mixture. The reaction mixture was stirred at -60° C. for 5 minutes and at room temperature for 30 minutes, and diluted with dichloromethane. The reaction mixture was washed successively with water, dilute hydrochloric acid and again water, dried over anhydrous sodium sulfate and evaporated to give N-p-nitrobenzyloxycarbonyl-4-formylpiperidine.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:25])[NH:6][C:7]1[N:8]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:9]=[C:10]([C:12]([CH2:16][F:17])([CH3:15])[CH2:13][F:14])[CH:11]=1.CCN(C(C)C)C(C)C.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([O:50][C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]([NH2:61])=[CH:53][N:52]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].O>CS(C)=O>[C:37]([O:41][C:42]([N:44]1[CH2:45][CH2:46][CH:47]([O:50][C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]([NH:61][C:5]([NH:6][C:7]3[N:8]([C:18]4[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=4)[N:9]=[C:10]([C:12]([CH2:16][F:17])([CH3:15])[CH2:13][F:14])[CH:11]=3)=[O:25])=[CH:53][N:52]=2)[CH2:48][CH2:49]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncc(N)c3ccccc23)CC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Add [5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Preparation 27, 2.7 mmol, 1.2 g) and DIPEA (2.9 mmol, 0.5 mL) to a solution of 4-(4-amino-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 22, 2.9 mmol, 1.0 g) in 4 mL of DMSO and stir at 85° C. overnight. Cool down, add water and extract with dichloromethane. Combine the organic layers and wash with saturated aq. sodium chloride. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate in gradient (from 15 to 70%) to yield 4-(4-{3-[5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS ES+ (m/z) 635 [M+H].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])[N:13]=[C:7]2[CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O.CO>[CH3:19][C:18]1[O:17][N:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]=1[C:12]1[N:13]=[C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][N:8]2[CH:11]=1
Reactant: COC(=O)c1ccn2cc(-c3c(-c4ccccc4)noc3C)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a solution of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (1.2 g, 3.6 mmol) in THF (9.9 mL), water (9.9 mL) and methanol (2.2 mL) was added lithium hydroxide monohydrate (302 mg, 7.2 mmol) and the resulting mixture stirred vigorously overnight. The mixture was then evaporated and acidified with hydrochloric acid (1 N) and then extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to leave a yellow solid. Purification by trituration with heptane afforded the title compound (764 mg, 66%) which was obtained as a yellow solid. MS: m/e=318.1 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:16]OC1C=C(CC(Cl)=O)C=CC=1OC.COC1C=C(CC(O)=O)C=CC=1OC>C(=S)=S>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]([CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C)cc1OC
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Agent: COc1ccc(CC(=O)O)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1cccc(C)c1OC
Reaction time: 8 h
Yield: 80 %

Procedure:
To a stirred solution of 35.6 g (0.24 mole) of 3,4-dimethoxytoluene and 14.6 g (0.11 mole) AlCl3 in 200 ml CS2 there was added dropwise over the course of 1 hr. 0.1 mole 3,4-dimethoxyphenylacetyl chloride (freshly prepared from 3,4-dimethoxyphenylacetic acid). The mixture was stirred overnight at 25°, poured into ice, and the resulting oil extracted into benzene. The extracts were dried and evaporated to yield a black viscous oil from which excess dimethoxytoluene was distilled in vacuo. After the pot residue had cooled, alcohol was added and the mixture was allowed to stand 24 hr at 0°. This allowed isolation of essentially pure ketone 4,5-dimethoxy-2-(3,4-dimethoxyphenylacetyl) toluene as a brown powder (25.4 g or 80% yield based upon the acid chloride). An analytical sample was recrystallized from EtOH-EtOAc to yield 4,5-dimethoxy-2-(3,4-dimethoxyphenylacetyl) toluene as white needles, mp 115°. Nmr (δ): 2.52 (s, 3H), 3.82 (s, 6H), 3.85 (s, 3H), 3.88 (s, 3H), 4.15 (s, 2H), 6.68 (s, 1H), 6.77 (s, 3H), 7.30 (s, 1H). Anal. Calcd for C19H22O5 : C, 69.07; H, 6.71. Found: C, 68.84; H, 6.93.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:5][N:4]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:24]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[O:5][N:4]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1Cc2c(-c3nc(CN)no3)ncn2-c2ccccc2C1=O
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1Cc2c(-c3nc(CNCc4ccccc4)no3)ncn2-c2ccccc2C1=O

Procedure:
0.93 g (3 mmol) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature overnight with 0.51 g (3 mmol) of benzyl bromide and 0.52 g (4 mmol) of N-ethyldiisopropylamine in 10 ml of methylene chloride. By evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 6/1 there was obtained 3-(3-benzylaminomethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride (0.25 g: 17%) of m.p. 195°-198°.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[O:28][CH2:29][CH3:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH2:29]([O:28][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:19]=1[NH:18][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1)[C:23]([OH:25])=[O:24])[CH3:30]
Reactant: CCOc1cc(C(=O)O)ccc1N
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)CC(C)O
Product: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Yield: 13.8 %

Procedure:
10-Chloro-6-methyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 10; 625 mg, 2.45 mmol), 4-amino-3-ethoxybenzoic acid (Intermediate 164; 509 mg, 2.82 mmol) and 4-toluenesulphonic acid mono hydrate (1.17 g, 6.13 mmol) were heated at 140° C. in 4-methyl-2-pentanol (15 mL) for 1.5 hours. The mixture was cooled and filtered to yield the title compound as a white solid (135 mg, 14%). The filtrate was absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (1%-3% MeOH/DCM) to yield the title compound as a white solid (115 mg, 12%)
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[O:12]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:13]1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:19](=[O:20])/[CH:18]=[CH:17]/[C:14]1[CH:15]=[CH:16][O:12][CH:13]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1ccoc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccoc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(3-furyl)propenoicacid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 247 (MH+).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.[CH3:47][S:48](Cl)(=[O:50])=[O:49].C(N(CC)CC)C>O1CCCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][S:48]([CH3:47])(=[O:50])=[O:49])=[CH:42][CH:41]=2)=[N:17]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 28 %

Procedure:
The title compound was prepared as described in Example 376, using 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.258 g, 0.43 mmol) in tetrahydrofuran (4.5 mL) was added methanesulfonyl chloride (0.05 mL, 0.64 mmol) and triethylamine (0.30 mL, 2.14 mmol). The final crude product was purified by preparative HPLC (10–100% acetonitrile to H2O, 20 min.) (0.042 g, 28% yield): 1H NMR (CD3OD) δ 7.93 (dd, 1H), 8.54 (br s, 1H), 8.29 (dd, 1H), 8.20 (m, 2H), 7.87 (dd, 1H), 7.62 (m, 2H), 3.23 (s, 3H); ES-MS (m/z) 355 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[CH3:23][NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.CCN(C(C)C)C(C)C>CC#N.[OH-].[Na+].CCOC(C)=O>[CH2:9]([S:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:24]([CH3:23])[CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:7]=1)[CH3:10]
Reactant: CNCC1CCCCO1
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCSc1nc(N(C)CC2CCCCO2)cc(C)c1C(=O)NCc1cccc(F)c1
Yield: 37.3 %

Procedure:
A solution of 254 mg (0.75 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2), 322 mg (2.25 mmol) N-methyl-1-(tetrahydro-2H-pyran-2-yl)methanamine and 392 μl (2.25 mmol) DIPEA in MeCN (2 ml) was heated in the microwave at 150° C. for 4.5 h. Subsequently the RM was diluted with a 2M aq. NaOH sol and EtOAc and the layers were separated. The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) provided 122 mg (0.28 mmol, 38%) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-[methyl-(tetrahydro-pyran-2-yl-methyl)-amino]-pyridine-3-carboxylic acid amide (example 5). [M+H]+ 432.2.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH:32][C:33]3[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=3)[C:36](OCC)=[O:37])(=[O:31])=[O:30])=[CH:27][C:21]=2[S:20](=[O:45])(=[O:44])[N:19]=1.[OH-].[NH4+:47]>>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH:32][C:33]3[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=3)[C:36]([NH2:47])=[O:37])(=[O:31])=[O:30])=[CH:27][C:21]=2[S:20](=[O:45])(=[O:44])[N:19]=1
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)Nc2ccc3c(c2)S(=O)(=O)N=C(c2c(O)c4cccnc4n(CCC(C)C)c2=O)N3)c1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)Nc4cccc(C(N)=O)c4)ccc3N2)c(O)c2cccnc21

Procedure:
A solution of the product of Example 454 (7.6 mg, 0.012 mmol) in 1 mL of ammonium hydroxide was stirred at 25° C. for 17 hours. The solvent was evaporated under a stream of warm nitrogen to provide the title compound (7.4 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.96 (d, J=6.62 Hz, 6 H) 1.47 (m, 2 H) 1.64 (m, 1 H) 4.30 (m, 2 H) 7.14 (m, 1H) 7.28 (m, 6 H) 7.43 (s, 1 H) 7.49 (d, J=7.72 Hz, 1 H) 7.66 (s, 1 H) 7.87 (s, 1 H) 8.36 (dd, J=7.54, 1.65 Hz, 1 H) 8.54 (s, 1 H) 10.45 (bs, 1 H) 10.51 (bs, 1 H) 15.89 (bs, 1 H).
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:17]=2)[CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[C:21]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([C:9]([OH:10])=[O:8])[CH2:20][CH2:19]2)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: [H][H]
Reactant: CCCCCCCCCC(=O)c1ccc2c(c1)CCC(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)c1ccc2c(c1)CCC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.1 %

Procedure:
50 mL of a THF solution containing 3.79 g (8.69 mmol) of 6-decanoyl-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid benzyl ester and 0.43 g of 5% palladium/carbon was placed in a hydrogen atmosphere, using a baloon, and was stirred at room temperature for 24 hours. The reaction mixture was filtered and by concentrating the filtrate, there was obtained 3.19 g of 6-decanoyl-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid. The yield was 100%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][OH:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](COC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 141.1 %

Procedure:
To a stirred solution of 2.32 g (0.012 mol) of p-toluensulfonic acid and 0.95 g (0.012 mol) of pyridine in 250 mL of dichloromethane, 25.0 g (0.12 mol) of Intermediate 1 was added. Then, 24.22 g (0.29 mol) of dihydropyran was added dropwise and the resulting mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the residue was redissolved in ethyl acetate (350 mL). The organic phase was washed with water (2×250 mL) and dried over sodium sulphate. The solvent was evaporated under vacuum and 49.00 g of a pale yellow oil was obtained. The oil was not purified and used directly in the following step.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:25][CH2:26][C:27]([NH2:29])=[O:28].CCCCCCC>C(OCC)(=O)C.O>[NH2:29][C:27](=[O:28])[CH2:26][NH:25][C:9]([CH:1]1[C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:2]1)=[O:11]
Reactant: NCC(N)=O
Reactant: O=C(O)C1CC12CCCCC2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)CNC(=O)C1CC12CCCCC2
Temperature: 65 °C
Reaction time: 2 h

Procedure:
The product from Example 1B (420 g, 2.72 mol) and 1,1′-carbonyldiimidazole (530 g, 3.27 mol) were combined in ethyl acetate (8.9 Kg) at ambient temperature and stirred for 2 hours. The mixture was treated with water (50 mL) and 2-aminoacetamide hydrochloride (368 g, 3.27 mol, purchased from Aldrich), heated at 65° C. for 10 hours, allowed to cool to room temperature, diluted with H2O (4.9 Kg) and heptane (1.35 Kg), and cooled to 10° C. resulting in formation of a solid. The solid was collected by filtration and washed with a mixture of H2O (440 g) and ethyl acetate (350 g). The resulting wet cake was slurried with H2O (2.0 Kg), filtered (550 g heptane wash) and dried to afford the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 8.10 (t, 1H), 7.21 (s, 1H), 6.95 (s, 1H), 3.62 (dq, 2H), 1.1-1.6 (m, 11H), 0.85 (dd, 1H), 0.61 (dd, 1H); 13C NMR (CDCl3, 100 MHz) δ 171.2, 170.8, 42.0, 36.9, 28.2, 26.7, 25.8, 25.2, 18.1; MS m/z 211 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:57]1([N:60]2[CH:65]3[CH2:66][CH2:67][CH2:68][CH:61]2[CH2:62][CH:63]([NH2:69])[CH2:64]3)[CH2:59][CH2:58]1>CN(C=O)C.O>[CH:57]1([N:60]2[CH:65]3[CH2:66][CH2:67][CH2:68][CH:61]2[CH2:62][CH:63]([NH:69][C:16]([C:12]2[N:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]5[C:2]([F:1])=[CH:22][CH:21]=[CH:20][C:19]=5[F:23])[C:7]4=[N:14][C:13]=2[CH3:15])=[O:18])[CH2:64]3)[CH2:59][CH2:58]1
Reactant: NC1CC2CCCC(C1)N2C1CC1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1CC2CCCC(C1)N2C1CC1
Reaction time: 0.25 h

Procedure:
70 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (0.22 mmol), 209 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU, 0.55 mmol) and 85 mg of N,N-diisopropylethylamine (0.66 mmol) were initially charged in 1.5 ml of DMF and stirred for 15 min. 59 mg of 9-cyclopropyl-9-azabicyclo[3.3.1]nonane-3-amine (0.33 mmol) were added, and the mixture was stirred at RT overnight. The mixture was then stirred overnight once more, at 60° C. 12 ml of water were added to the reaction solution, and the precipitate formed was filtered off, washed with water and dried. The residue formed was purified by silica gel chromatography (mobile phase: dichloromethane/methanol 40:1). This gave 60 mg of the title compound (53% of theory, purity 94%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](Cl)(=O)C>CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A 1 L 3-necked round bottomed flask equipped with a nitrogen inlet, stirbar, addition funnel and thermocouple was charged with 4-fluoro-3-nitrobenzoic acid (50 g, 0.27 mol) and methanol (300 mL). The system was cooled to 0 C and acetyl choride (27 mL, 0.37 mol) was added dropwise. The system was warmed to room temperature, the addition funnel was replaced with a reflux condensor, and was heated to reflux for 1.5 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate. The organic extract was washed with brine, dried with Na2SO4 and concentrated in vacuo to give methyl 4-fluoro-3-nitrobenzoate as an orange solid (40.6 g, 75%). 1H NMR (400 MHz, CD3OD) δ 8.67 ((dd, J=2.2 and 6.8 Hz, 1H), 8.34 (dddd, J=2.2, 4.4, 6.4 and 8.8 Hz, 1H), 7.55 (dd, J=8.8 and 10.8 Hz, 1H), 3.94 (s, 3H) ppm. ES-HRMS m/z 200.02446 (M+H calcd for C8H7FNO4 requires 200.0354). Step 2 Preparation of methyl 3-amino-4-fluorobenzoate