Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.O[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[CH2:25][CH2:24][CH2:23]2>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:20]2[CH:29]=[CH:28][C:27]3[C:26](=[O:30])[CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)CCCC3=O)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 6-hydroxy-1,2,3,4-tetrahydronaphtalenone and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
(S)-(1-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (260 mg, 0.55 mmol), triethylamine (111 mg, 1.1 mmol), and benzoyl chloride (93 mg, 0.66 mmol) were dissolved in dichloromethane (2 ml) and stirred overnight. The reaction mixture was then poured on HCl (1N), and extracted with dichloromethane. The organic layer was washed with NaHCO3 (1N), dried, and evaporated. (S)-(5-Benzoyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester was obtained in sufficient purity for the next step.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](Cl)=[O:11].[OH:13][C:14]12[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[C:18]1([NH:27][C:28](=[O:30])[CH3:29])[C:17]1[CH:31]=[CH:32][C:33]([CH:35]([CH3:37])[CH3:36])=[CH:34][C:16]=1[O:15]2>C1COCC1>[C:10](=[O:11])([O:9][CH3:8])[O:15][C:16]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:17]=1[C:18]1([NH:27][C:28](=[O:30])[CH3:29])[C:19](=[O:26])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]1=[O:13]
Reactant: CC(=O)NC12C(=O)c3ccccc3C1(O)Oc1cc(C(C)C)ccc12
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Oc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.1 %

Procedure:
Triethylamine (0.24 ml, 1.77 mmol) and methylchloroformate (0.11 ml, 1.48 mmol) were added to N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)acetamide (0.50 g, 1.48 mmol) in THF (5 ml). The reaction mixture was stirred at room temperature for 12 hrs, concentrated in a vacuum to remove solvent. The reaction mixture was extracted with water and methylene chloride, and purified through silica gel column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.10 g, 14%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:36][N:35]([CH3:37])[CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)CCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 21 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-dimethylamino-ethoxy)-ethyl]-amide (25 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (93 mg), [2-(2-amino-ethoxy)-ethyl]-dimethyl-amine (60 mg), HBTU (103 mg), and DIEA (59 uL). LC/MS: m/z 523.0.
Reaction SMILES: C([O:4][C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]2[C:14]3=[N:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][C:18]([CH3:19])=[C:13]3[N:12]=[C:11]2[CH3:24])=[C:7]([Cl:27])[CH:6]=1)(=O)C.S(=O)(=O)(O)O.CO>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:27][C:7]1[CH:6]=[C:5]([OH:4])[CH:26]=[CH:25][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=[C:11]1[CH3:24]
Reactant: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc(OC(C)=O)cc3Cl)c2n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc(O)cc3Cl)c2n1
Yield: 65.7 %

Procedure:
A mixture of methyl 3-(4-acetoxy-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (6.5 g), conc. sulfuric acid (3.0 ml) and methanol (60 ml) was refluxed under heating for 1.5 hr. The reaction mixture was diluted with chloroform (60 ml) and saturated aqueous sodium hydrogen carbonate solution was gradually added under ice-cooling. The organic layer was separated, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was washed with diethyl ether to give methyl 3-(2-chloro-4-hydroxybenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (3.81 g) as a pale-yellow powder.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][N:15]([C:17]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][CH:13]([C:25](O)=[O:26])[CH2:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].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.O[N:62]=[C:63]([O:65][CH2:66][CH3:67])[NH2:64]>CN(C)C=O>[F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:12][CH:13]([C:25]3[O:26][N:64]=[C:63]([O:65][CH2:66][CH3:67])[N:62]=3)[CH2:14][N:15]([C:17]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)=[O:18])[CH2:16]2)=[CH:7][CH:6]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Reactant: CCOC(N)=NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1noc(C2CC(c3ccc(C(C)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 150 mg (0.376 mmol, 2:1 cis/trans isomer mixture) of the carboxylic acid from Example 73A in 5.2 ml of N,N-dimethylformamide were added, at RT, 172 mg (0.452 mmol) of HATU and 0.14 ml (0.83 mmol) of N,N-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 43.1 mg (0.414 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at room temperature for 2 h. The reaction solution was purified directly by means of preparative HPLC. The resulting intermediate (118 mg) was taken up in toluene (24 ml), admixed with 4 Å molecular sieve and stirred under reflux overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by means of preparative HPLC. Yield: 55.4 mg (32% of theory)
Reaction SMILES: [Br:1]C1(Br)NC(=O)NC1=O.[Cl:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[C:12]=1[CH3:21].CC(N=NC(C#N)(C)C)(C#N)C.CC(=O)OCC>ClC1C=CC=CC=1>[Cl:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[C:12]=1[CH2:21][Br:1]
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O=C1NC(=O)C(Br)(Br)N1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Reaction time: 1 h

Procedure:
A mixture of dibromohydantoin (70 g, 0.24 mol) and AlBN (5 g) was added in portions at 150° C. to 2,6-dichloro-3-nitrotoluene (100 g, 0.48 mol) in chlorobenzene (400 ml). After 1 h, a mixture of dibromohydantoin (35 g, 0.12 mol) and AIBN (2.5 g) was again added. After a further 1.5 h, the mixture was allowed to cool and EA (500 ml) was added. This mixture was washed once each with saturated Na2SO3, Na2CO3 and NaCl solution, dried (MgSO4) and concentrated, the title compound being obtained as an amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([O:24][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[C:6]([F:8])[CH:7]=1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1nccn1-c1ccc(N)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nccn1-c1ccc(NC(=O)OCc2ccccc2)cc1F
Reaction time: 16 h
Yield: 93.5 %

Procedure:
5-Amino-2-(2-methylimidazol-1-yl)fluorobenzene (34.25 g, 0.179 M) was dissolved in dry dichloromethane (600 ml) under nitrogen, and cooled to −5°. Pyridine (17.7 g, 0.224 M) was added, followed by benzyl chloroformate (33.7 g, 0.197 M) over 20 minutes. The mixture was stirred and the temperature allowed to rise to ambient over 16 hours. Aqueous sodium bicarbonate (5%, 250 ml) was added, the organic layer separated, the aqueous layer re-extracted with dichloromethane (2×300 ml), and combined extracts dried (magnesium sulfate). After filtration and evaporation, the residue was recrystallised from toluene (400 ml) to give title product (54.5 g). NMR (DMSO-d6) δ: 2.13 (s, 3H); 5.18 (s, 2H); 6.89 (s, 1H); 7.17 (s, 1H); 7.41 (overlapping m, 7H); 7.73 (dd, 1H); 10.21 (br, 1H). MS (ESP): 326 (MH+) for C18H16FN3O2
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)([CH3:12])[CH3:11].[Br:26][C:27]1[N:32]2[N:33]=[CH:34][N:35]=[C:31]2[C:30](Br)=[N:29][CH:28]=1>CC(O)C>[Br:26][C:27]1[N:32]2[N:33]=[CH:34][N:35]=[C:31]2[C:30]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([CH:16]3[CH2:15][CH2:14][N:13]([CH:10]([CH3:12])[CH3:11])[CH2:18][CH2:17]3)=[CH:24][CH:23]=2)=[N:29][CH:28]=1
Reactant: CC(C)N1CCC(c2ccc(N)cc2)CC1
Reactant: Brc1ncc(Br)n2ncnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)N1CCC(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)CC1

Procedure:
N,N-Diisopropylethylamine (200 μL, 1.2 mmol) is added to a mixture of 4-(1-isopropylpiperidin-4-yl)phenylamine (220 mg, 1.0 mmol) and 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (280 mg, 1.0 mmol) in iPrOH (5 mL) and heated at reflux for 48 h. The mixture is cooled and the solvent evaporated under reduced pressure to afford an orange-brown solid. This is partitioned between DCM (50 mL) and water (20 mL) and the layers are separated. The organic phase is washed with citric acid (10% aq., 3×25 mL). The combined washings are extracted with DCM (25 mL) and then made basic by addition of NaHCO3 (s). The mixture is extracted with DCM (3×25 mL) and the combined extracts dried over MgSO4 and evaporated. The crude product was purified by chromatography on silica gel, eluting with 5%-10% MeOH in DCM to afford the desired compound, contaminated with the starting aniline. This was recrystallised from MeOH to afford the pure title compound (110 mg).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([CH2:12][NH2:13])[OH:11]>>[OH:11][CH2:10][CH2:12][NH:13][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: NCCO
Product: N#Cc1ccccc1NCCO

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and ethanolamine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:15](=[C:16]([O:32][CH3:33])[C:17]5[C:22]([CH:23]=4)=[N:21][C:20]([C:28]([F:31])([F:30])[F:29])=[CH:19][CH:18]=5)[N:14]=3)=[CH:11][C:10]([C:34]([F:37])([F:36])[F:35])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:38][NH2:39]>C1COCC1>[CH3:38][NH:39][C:25]([C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:28]([F:29])([F:30])[F:31])=[N:21]2)=[C:16]([O:32][CH3:33])[C:15]=1[NH:14][C:13]([C:12]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=[C:10]([C:34]([F:35])([F:37])[F:36])[CH:11]=1)=[O:26])=[O:27]
Reactant: COc1c2ccc(C(F)(F)F)nc2cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc2nc(C(F)(F)F)ccc2c(OC)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl

Procedure:
2-[2-(3-Chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-9-methoxy-6-trifluoromethyl-3-oxa-1,5-diaza-anthracen-4-one is reacted with methylamine in THF analogously to the procedure given in step i) of example H-18. The title product is obtained as yellow crystals after flash column chromatography eluting with 1:1 hexane:ethyl acetate. m.p.: 209-211° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:22])[NH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1.Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[NH:16][C:15]4[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=4[S:13][C:12]=3[CH:11]=[N:10][C:9]=2[OH:22])=[CH:6][CH:7]=1
Reactant: O=c1[nH]cc2c(c1-c1ccc(Cl)cc1)Nc1ccccc1S2
Agent: Cl
Solvent: CO
Product: Oc1ncc2c(c1-c1ccc(Cl)cc1)Nc1ccccc1S2

Procedure:
To a solution of 1 part 4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one in 25 parts of concentrated hydrochloric acid is added 25 parts methanol. The solution is warmed to the mean boiling point of the alcohol. Another 50 parts of methanol is added and heating continued until nearly all the solid material is dissolved. The hot solution is filtered to remove undissolved solids and upon concentrating the solution volume of filtrate in a suction flask, yellow needles of 4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3-ol hydrochloride result, melting above 300° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:34]([N:30]1[CH2:31][CH2:32][CH:27]([N:12]2[C:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[C:17]=4[N:16]=[CH:15][C:14]=3[C:25](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[C:11]2=[O:33])[CH2:28][CH2:29]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(C(=O)c4ccccc4)CC3)c12

Procedure:
1-(1-Benzoyl-piperidin-4-yl)-3-(3-chloro-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (51 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and benzoyl chloride. LCMS: m/z 541 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([CH:10]=[O:11])[CH2:3]1.[CH3:13][Mg]Br>C1COCC1>[CH3:9][C:6]1([CH3:8])[CH2:7][C:2]([CH3:12])([CH3:1])[CH2:3][CH:4]([CH:10]([OH:11])[CH3:13])[CH2:5]1
Reactant: C[Mg]Br
Reactant: CC1(C)CC(C=O)CC(C)(C)C1
Solvent: C1CCOC1
Product: CC(O)C1CC(C)(C)CC(C)(C)C1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
The crude 3,3,5,5-Tetramethyl-cyclohexanecarboxaldehyde (650 mg, 3.8 mmol) was treated with methylmagnesium bromide (4.5 mmol, 1.2 eq) in THF (20 mL) at 0° C., and allowing to warm to RT following a method analogous to General Procedure I to produce 1-(3,3,5,5-tetramethyl-cyclohexyl)-ethanol (400 mg) after quenching the reaction at 0° C. with 2N HCl, extraction of the product with EtOAc, and evaporation of the solvent under vacuum. The crude material was used without purification in the next step.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Yield: 50.8 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (50 mg, 0.16 mmol), 4-aminobutyric acid (832 mg, 8.06 mmol) and NaOMe solution (12 mL, 6.05 mmol, 0.5 M in MeOH) was refluxed for 48 h. Solvent was evaporated in vacuo, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+2% AcOH) to give 31 mg of the title compound as a light yellow solid. MS: (+) m/z 382.01 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:17][CH3:18])=[C:6]([C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)[C:7]([OH:9])=O)[CH2:2][CH3:3].S(Cl)(Cl)=O.[CH2:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][NH2:31])[CH3:24].O(C(C)C)C(C)C>>[CH2:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][NH:31][C:7](=[O:9])[C:6]1[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]=1[O:17][CH3:18])[CH3:24]
Reactant: CCN1CCC[C@H]1CN
Reactant: CCCc1cc(OC)c(OC)c(C(=O)O)c1OC
Solvent: O=S(Cl)Cl
Solvent: CC(C)OC(C)C
Product: CCCc1cc(OC)c(OC)c(C(=O)NC[C@@H]2CCCN2CC)c1OC

Procedure:
3-Propyl-2,5,6-trimethoxybenzoic acid (23 g, 0.09 mol) was treated with thionyl chloride and (2S)-(-)-1-ethyl-2-aminomethylpyrrolidine as described in example 4. Yield 10.6 g (32%). M.p. 68°-70° C. (i-Pr2O). 1H-NMR (CDCl3): δ6.73 (s,1H), 6.40 (b,1H), 3.85 (Sx2,6H), 3.76 (s,3H), 0.9-3.8 (m,21H)ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1)(=[O:19])=[O:18]>>[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:25][CH:24]=[CH:23][N:22]=1)(=[O:18])=[O:19]
Reactant: O=S(=O)(Nc1nccnc1Cl)c1cccc(Cl)c1Cl
Reactant: OCc1cccnc1
Product: O=S(=O)(Nc1nccnc1OCc1cccnc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 28 using pyridine-3-methanol (0.09 g) and 2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (0.1 g). Yield 0.042 g.
Reaction SMILES: [NH2:1]/[C:2](=[N:28]\[OH:29])/[CH2:3][CH2:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)[N:9]=[N:8][C:7]=1[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23].[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:25]1([NH:24][C:22]([C:7]2[N:8]=[N:9][N:10]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:16]=3)[C:6]=2[CH2:5][CH2:4][CH2:3][C:2]2[NH:1][C:30](=[O:31])[O:29][N:28]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC/C(N)=N/O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCc2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
To a solution of 5-[(4Z)-4-amino-4-(hydroxyimino)butyl]-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (240 mg, 0.6 mmol) obtained in Example 1209 and 1,1′-carbonyldiimidazole (97 mg, 0.6 mmol) in THF (5 ml) was added DBU (91 mg, 0.6 mmol) at room temperature and the mixture was stirred at 50° C. for 3 hr and concentrated. The residue was dissolved in water (10 ml), adjusted to pH 4-5 with 1N hydrochloric acid and liberated oil was extracted with ethyl acetate (30 ml×2). The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a colorless powder (150 mg, 59%).
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[O:6].[CH3:8][Si:9]([CH3:23])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]1[CH:11]=[C:12](O)[CH:13]=[CH:14][CH:15]=1.S(OC)(OC)(=O)=O>O>[CH3:8][Si:9]([CH3:23])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]1[CH:11]=[C:12]([O:6][CH3:5])[CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: CCCCCC[Si](C)(C)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCCCCC[Si](C)(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a 0° C. slurry of 3.98 g. (0.166 mole) of sodium hydride in 50 ml. dimethylformamide was slowly added a solution of 26.1 g. (0.111 mole) of 3-(dimethyl-n-hexylsilyl)phenol in 50 ml. dimethylformamide. Following addition, the reaction mixture was stirred 1 hr at 25° C. and cooled to 0° C. To the cooled reaction mixture, 20.9 g. (0.166 mole) of dimethyl sulfate was slowly added. Following addition, the reaction was stirred for 2 hr at 25° C. and then added to 200 ml. water. The quenched reaction mixture was extracted with three 100 ml. portions of hexane. The hexane extract was dried over anhydrous magnesium sulfate and evaporated to an oil. This oil was purified by column chromatography on 500 g. of silica gel eluted with 1% diethyl ether hexane to yield 14.8 g. (53%) of the title compound as an oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2.[I:24]I>O1CCCC1>[F:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[I:24])=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: II
Reactant: Fc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Fc1cnc2ccccc2c1I
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 41.4 %

Procedure:
To a 0° C. solution of diisopropyl amine (2.8 mL, 27 mmol) in tetrahydrofuran (80 mL) was added dropwise butyl lithium (8.1 mL, 2.5 M solution in hexane, 27 mmol). After 10 min., the flask was cooled to −78° C. and 3-fluoro quinoline from Step B (3 g, 20 mmol) in 20 mL of tetrahydrofuran was added over 15 min. period. The stirring was continued for an additional 4 h., after which iodine (5.4 g, 21 mmol) in 10 mL of THF (tetrahydrofuran) was added and the reaction temperature was maintained at −78° C. for additional 2 h. The reaction was quenched by adding a mixture of water and tetrahydrofuran (25 mL, 1:9), and the resulting solution was extracted with ethyl acetate. The organic layers were combined, washed with water and brine. Purification by silica gel column gave the title compound (2.26 g, 40%). MS (ES) 148.1 (M+H)+.