Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:3]=1[NH:4][CH2:5][CH2:6][O:7][Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:3]=1[NH:4][CH2:5][CH2:6][OH:7]
Reactant: Cc1cccc(NCCO[Si](C)(C)C(C)(C)C)c1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cccc(NCCO)c1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 50-mL RBF was added 2-bromo-N-(2-(tert-butyldimethylsilyloxy)ethyl)-3-methylaniline (1.43 g, 4.15 mmol) and THF (10 mL). A solution of TBAF (1.0M in THF; 4.98 mL, 4.98 mmol) was added dropwise at RT. The reaction mixture was allowed to stir for 1.5 h at RT. The solvent was removed under reduced pressure. The remaining residue was purified by flash chromatography (5-60% EtOAc/hexanes). 2-(2-Bromo-3-methylphenylamino)ethanol was isolated as a clear yellow oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]=2[N:3]=1.[Cl:19]C1C=C2C(C3OC4C=CC=CC=4C=3N=C2O)=CC=1>>[Cl:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]=2[N:3]=1
Reactant: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Reactant: Oc1nc2c3ccccc3oc2c2ccccc12
Product: Clc1nc2c3ccccc3oc2c2ccccc12

Procedure:
The procedure was similar to step S19C, while the starting material was 22B in stead of 19B.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[C:18]([OH:20])=[O:19])[CH:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][CH2:33][NH2:34])[CH:28]=[C:29]([F:31])[CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([CH2:32][CH2:33][NH:34][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=3)[CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[C:18]([OH:20])=[O:19])[CH:5]=[CH:4][N:3]=2)[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: O=C(O)C1CNCCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1cc(F)cc(F)c1
Product: O=C(O)C1CNCCN1Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1

Procedure:
Intermediate 137 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 454. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.47 (s, 1H) 8.36 (d, 1H)) 8.33 (d, 1H) 7.87 (d, 1H) 7.71 (t, 1H) 7.65 (d, 1H) 7.00 (d, 2H) 6.77 (s, 1H) 4.63 (dd, 1H) 4.36 (s, 2H) 4.08 (t, 2H) 3.84 (dd, 2H) 3.65 (t, 2H) 3.47 (t, 2H) 3.09 (t, 2H).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.S(=O)(=O)(O)O>>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:15]([O:17][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:16])[CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Product: CC(C)(C)OC(=O)C1(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isobutylene (80.0 mL, 0.847 mol) was passed through a mixture of 1-(4-bromophenyl)cyclopropanecarboxylic acid (10.0 g, 0.0415 mol, example 238, step 1) and sulfuric acid (1.0 mL, 0.019 mol) at −78° C. The mixture was sealed and was stirred at room temperature overnight. The isobutylene was evaporated at room temperature and the residue was dissolved in ethyl acetate (100 mL), and washed with water and brine successively. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[NH:14][C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1.S(OC)(O[CH3:29])(=O)=O.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([CH3:29])[C:13]2=[O:23])=[C:4]([F:24])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(C)Oc1cc(-n2c(=O)[nH]c3c(c2=O)CCCC3)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(-n2c(=O)c3c(n(C)c2=O)CCCC3)c(F)cc1Cl

Procedure:
usinq 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione with dimethyl sulphate and sodium hydride in dimethylformamide there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-1-methyl-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione, m.p. 143°-145° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:15][CH3:16])[CH2:11][C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.C(OC(C)C)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].CC(C)([O-])C.[Li+]>C1COCC1>[CH2:30]([O:29][C:27](=[O:28])[NH:14][C:12](=[O:13])[CH2:11][C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:4][CH:5]=1)[CH2:15][CH3:16])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC[C@H](CC(N)=O)Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CC[C@H](CC(=O)NC(=O)OCc1ccccc1)Nc1ccc(C(F)(F)F)cc1
Temperature: -12 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A clean, dry and nitrogen gas purged flask was charged with (3R)-3-(4-trifluoromethyl-phenylamino)-pentanoic acid amide (20.11 g, 77.27 mmol) and isopropyl ether (100 mL) and the mixture was cooled to −12° C. Benzyl chloroformate (13.25 mL, 92.8 mmol) was then added followed by the slow addition of 1.0 M lithium tert-butoxide in THF solution (185.5 mL). The lithium tert-butoxide solution was added at such a rate that the internal temperature remained below 0° C. Fifteen minutes after the completion of base addition, the reaction was quenched by adding the mixture to isopropyl ether (100 mL) and 1.5 M hydrochloric acid (130 mL). The phases were separated and the organic layer was washed with saturated aqueous sodium chloride solution (130 mL). The phases were separated, the organic layer was dried (MgSO4), filtered, and concentrated under partial vacuum (at 40° C.) to a total volume of 100 mL. Additional isopropylether (200 mL) was added and the solution was again concentrated under partial vacuum (at 40° C.) to a total volume of 100 mL. After cooling, the solution was seeded with (3R)-[3-(4-trifluoromethyl-phenylamino)-pentanoyl]-carbamic acid benzyl ester and allowed to stir at room temperature overnight. The remaining solvent was displaced with cyclohexane using partial vacuum distillation (45° C. bath, 200 mL followed by 100 mL), the resultant slurry was cooled and stirred for 40 minutes, filtered, and dried to provide 25.8714 g (85%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][CH2:27][CH2:28][CH3:29].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN1CCCC1=O>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][CH2:27][CH2:28][CH3:29])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1ccccc1
Yield: 39.5 %

Procedure:
Under a nitrogen atmosphere triethylamine (765 mg, 7.56 mmol) was added to a solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (50 mL). Benzoyl chloride (972 mg, 5.55 mmol) was added dropwise. When analysis by HPLC indicated that the reaction was complete, the reaction solution was poured into distilled water (500 mL). The pH was adjusted to 10 using solid potassium carbonate. A solid was isolated by filtration, rinsed with water and then dried in a vacuum oven. This material was stirred with chloroform (500 mL) and then filtered. The filtrate was loaded onto a silica gel column. The column was eluted with 1-5% methanol in chloroform. The purified material was dried in a vacuum oven to provide 800 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide as a solid, m.p. 189.4-190.0° C. Analysis: Calculated for C24H27N5O. 0.82H2O: % C, 69.25; % H, 6.93; % N, 16.82; Found: % C, 69.50; % H, 7.15; % N, 17.02.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].O.[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1.O>CN(C=O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([NH:13][C:14]2[N:15]=[N:16][NH:17][N:18]=2)=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: Nc1nnn[nH]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(C(=O)Nc2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.4 %

Procedure:
To a solution of 4-carboxybenzaldehyde (40.2 g, 0.27 mol) in DMF (400 mL) was added N-ethyl-N′-3-dimethylaminopropylcarbodiimide (65.5 g, 0.33 mol) followed by 5-aminotetrazol monohydrate (36.6 g, 0.35 mol). The mixture was stirred for 24 hours at ambient temperature. The reaction volume was then reduced to one half by rotary evapoation, and water (800 mL) was added. The precipitate was collected by filtration, washed with cold acetonitrile and dried overnight in a vacuum oven to afford 46.0 g (80%) of 4-formyl-N-(2H-tetrazol-5-yl)benzamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2OC)=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.Br.[OH-:24].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:24])[NH:12][CH:11]=2)=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COc1ccncc1-c1cc(C#N)c(N)nc1-c1ccco1
Reactant: [OH-]
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cc(-c2ccc(=O)[nH]c2)c(-c2ccco2)nc1N

Procedure:
A solution of 2-amino-6-(2-furyl)-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile (1.0 g, 3.42 mmol) in acetic acid (6 ml)-conc. hydrobromic acid (10 ml) was stirred at 100° C. for 1.5 hours. After cooling as it was, the reaction solution was adjusted to pH 12 to 13 with 5 N sodium hydroxide and washed with ethyl acetate. The organic layer was extracted with 1 N sodium hydroxide (×2), and then the combined aqueous layer was neutralized with 5 N hydrochloric acid. The resulting solid was collected by filtration, to give the title compound (760 mg) as yellow crude crystals. After suspending the product in methanol, 4 N HCl/ethyl acetate was added thereto to dissolved and it subjected to silica gel column chromatography (elution solvent; dichloromethane, dichloromethane:methanol=40:1, 20:1, 10:1). The resulting crude objective compound was suspended in water, and then neutralized with 5 N sodium hydroxide. The solid was collected by filtration and washed with water, to give the title compound (486 mg, 51%) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:24][C@@H:25]1[CH2:29][N:28]([C:30](=[O:42])[CH2:31]OS(C2C=CC=CC=2)(=O)=O)[C@H:27]([C:43]#[N:44])[CH2:26]1>CN(C)C=O>[CH2:14]([O:13][C:11]([C:6]12[CH2:5][CH2:4][C:3]([NH:2][CH2:31][C:30]([N:28]3[CH2:29][C@@H:25]([F:24])[CH2:26][C@H:27]3[C:43]#[N:44])=[O:42])([CH2:10][CH2:9]1)[CH2:8][CH2:7]2)=[O:12])[CH3:15]
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Reaction time: 1 h
Yield: 92.4 %

Procedure:
Ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride (206 mg), potassium carbonate (243.2 mg), potassium iodide (13.3 mg) and N,N-dimethylformamide (5 mL) were mixed together. To this mixture, a solution of (2S,4S)-4-fluoro-1-[2-(benzenesulfonyloxy)acetyl]pyrrolidine-2-carbonitrile (250 mg) in N,N-dimethylformamide (1.5 mL) was added at 50° C. and the mixture was further stirred for 1 hour. Subsequently, the reaction mixture was concentrated under reduced pressure and the residue was purified on a silica gel column (eluant=ethyl acetate:methanol=20:1) to give (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carbonitrile as a white solid (260 mg, 92% yield).
Reaction SMILES: Cl[CH:2]([CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:21])([F:20])[CH:17]([Cl:19])[Cl:18])=[CH:11][CH:10]=1)(=[O:8])=[O:7])C#N.[CH2:22]([N:24](CC)CC)C>C1C=CC=CC=1>[Cl:19][CH:17]([Cl:18])[C:16]([F:20])([F:21])[O:15][C:12]1[CH:11]=[CH:10][C:9]([S:6]([C:5](=[CH2:2])[C:22]#[N:24])(=[O:7])=[O:8])=[CH:14][CH:13]=1
Reactant: CCN(CC)CC
Reactant: N#CC(Cl)CS(=O)(=O)c1ccc(OC(F)(F)C(Cl)Cl)cc1
Solvent: c1ccccc1
Product: C=C(C#N)S(=O)(=O)c1ccc(OC(F)(F)C(Cl)Cl)cc1

Procedure:
To 3.0 g (0.079 mol) of 2-chloro-3-((4-(2,2-dichloro-1,1-difluoroethoxy)phenyl)sulfonyl)propanenitrile in 100 ml of benzene was added a slight molar excess of triethylamine. The reaction mixture was filtered to remove the triethylamine hydrochloride produced. The benzene was removed in vacuo from the filtrate, and the residue which remained was crystallized from methanol/ water to give 1.5 g of the title compound as a tan solid, mp 89°-90° C.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14](S(C3C=CC=CC=3)(=O)=O)[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C@H:10]([OH:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]1C2C(=CC=CC=2)C=CC=1.[Li+]>C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C@H:10]([OH:25])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccc(F)cc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Agent: [Li+]
Agent: [c-]1cccc2ccccc12
Solvent: C1CCOC1
Product: O[C@@H]1CC[C@H]2CC[C@]1(c1ccc(F)cc1)N2Cc1ccccc1
Temperature: -78 °C
Yield: 72.5 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-1-(4-fluorophenyl)-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 14; 10.72 g, 23.77 mmol) was dissolved in THF (200 ml) then cooled to −78° C. and lithium naphthalenide added until a permanent green colour was observed. Each portion was then quenched with saturated ammonium chloride solution then extracted with ethyl acetate (×3) and the extracts dried (MgSO4) and concentrated in vacuo. The extracts were combined to give a yellow oil/solid. This was purified by flash column chromatography [20%-40% ethyl acetate in iso-hexane] to give a yellow solid which was repurified by flash column chromatography [25% ethyl acetate in iso-hexane] to give the title compound as a clear yellow oil (5.37 g, 73%).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[C:19]([NH:41][CH2:42][C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)=[N:20][N:21](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:15]=3[CH:14]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[C:1]1([C@H:7]([NH:9][C:10]([NH:12][C:13]2[N:18]=[CH:17][C:16]3[C:19]([NH:41][CH2:42][C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)=[N:20][NH:21][C:15]=3[CH:14]=2)=[O:11])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(NCc1cccnc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(NCc3cccnc3)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-1-(1-phenylethyl)-3-(3-((pyridin-3-ylmethyl)amino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (0.056 mmol) was taken up in TFA (1 ml) and the reaction mixture was stirred at room temperature for 1 h. Triethylsilane (0.009 ml, 0.056 mmol) was added drop wise, and the reaction mixture stirred for an additional 5 minutes. The mixture was concentrated, re-dissolved in DMSO (1.5 mL) and submitted for purification by mass-triggered preparative HPLC to afford (R)-1-(1-phenylethyl)-3-(3-((pyridin-3-ylmethyl)amino)-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. TFA (16.7 mg, 0.033 mmol, 59.5% yield) as a white solid. MS ESI calc'd. For C21H22N2O [M+H]+ 388. found 388. 1H NMR (ppm, 600 MHz, DMSO): δ 8.81 (s, 1H); 8.70 (s, 1H); 8.58 (d, J=5.0 Hz, 1H); 8.09 (s, 1H); 7.96 (s, 1H); 7.62 (s, 1H); 7.31-7.32 (m, 4H); 7.21 (t, J=6.6 Hz, 1H); 7.05 (s, 1H); 4.84 (t, J=7.2 Hz, 1H); 4.52 (s, 2H); 1.40 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].CO[CH:21]=[C:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][CH:21]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[CH3:27])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COC=C(C)C(=O)OC
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C(C)=CNC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
27.4 g of isopropyl 2-chloro-4-fluoro-5-ureidobenzoate and 13.0 g of methyl 3-methoxy-2-methyl-acrylate are heated under reflux for 2 hours in 250 ml of benzene with 1.9 g of toluene-4-sulphonic acid monohydrate. The reaction mixture is evaporated to dryness under reduced pressure and the residue is stirred with 400 ml of diethyl ether. The insoluble material is filtered off under suction and the filtrate is evaporated to dryness under reduced pressure. The residue is purified by chromatography on 1 kg of silica gel using ethyl acetate/n-hexane (1:3) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(methoxycarbonyl)propenyl]ureido}-benzoate, m.p. 189°-190° C.
Reaction SMILES: [S:1]=[C:2]1[NH:10][C:9]2[NH:8][CH:7]=[N:6][C:5]=2[C:4](=S)[NH:3]1.O.[NH2:13][NH2:14]>>[NH:13]([C:4]1[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[NH:10][C:2](=[S:1])[N:3]=1)[NH2:14]
Reactant: S=c1[nH]c(=S)c2nc[nH]c2[nH]1
Reactant: NN
Solvent: O
Product: NNc1nc(=S)[nH]c2[nH]cnc12
Temperature: 120 °C
Yield: 61 %

Procedure:
2,6-Dithioxo-1,2,3,6-tetrahydro-9H-purine (0.5 g, 2.7 mmol) was added to 80% hydrazine hydrate (5 ml), and the mixture was stirred with heat for 10 minutes at 120° C. After completion of reaction, crystals that precipitated were collected by filtration, and washed with water. The crystals were recrystallized from water to obtain 0.30 g (yield 61%) of colorless powdery crystals (m.p.=292° C. (decomposed)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]2[CH2:14][O:15][CH2:16][C@@H:12]2[N:11]2[N:17]=[C:18]([I:23])[C:19]([C:20]([OH:22])=O)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:26](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-]>CN(C=O)C.O>[C:20]([C:19]1[C:18]([I:23])=[N:17][N:11]2[C@H:12]3[CH2:16][O:15][CH2:14][C@H:13]3[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C:10]=12)(=[O:22])[NH2:26]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2[C@H]2COC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2[C@H]2COC[C@H]21
Reaction time: 12 h
Yield: 81.4 %

Procedure:
To a stirred solution of Intermediate 352E (0.480 g, 1.103 mmol) in DMF (10 mL) at RT was added DIPEA (0.963 mL, 5.51 mmol), HATU (0.839 g, 2.206 mmol), and NH4Cl (0.295 g, 5.51 mmol). After stirring for 12 h, the reaction mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated to afford Intermediate 352F (0.39 g, 74%) as a pale yellow oil. MS(ES): m/z=435 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.95 (s, 2H), 5.30-5.13 (m, 2H), 4.86 (dd, J=3.4, 7.6 Hz, 1H), 4.38 (d, J=15.9 Hz, 1H), 4.14-4.03 (m, 1H), 3.98-3.82 (m, 2H), 3.75 (dd, J=6.6, 9.3 Hz, 1H), 1.43 (s, 9H).
Reaction SMILES: O[C@:2]1([C:12]([OH:14])=[O:13])[CH2:6][CH2:5][C:4]([CH2:8][OH:9])([CH3:7])[C:3]1([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:7][C:4]12[C:3]([CH3:11])([CH3:10])[C@@:2]([C:12]([OH:14])=[O:13])([CH2:6][CH2:5]1)[O:9][CH2:8]2
Reactant: CC1(CO)CC[C@](O)(C(=O)O)C1(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC12CC[C@@](C(=O)O)(OC1)C2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 222A (125 mg) and triphenylphosphine (366 mg) in tetrahydrofuran (10 mL) at 0° C. was added dropwise diisopropylazodicarboxylate (0.27 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was partitioned between 1 N aqueous NaOH (10 mL) and ether (20 mL) and the layers separated. The aqueous phase was extracted twice with ether to remove non-polar organic extracts, then acidified with 1 N aqueous HCl and extracted with ether (3×). The organic extracts were dried (MgSO4), filtered and solvent evaporated to afford the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 0.93 (s, 3H), 0.95 (s, 3H), 1.04 (s, 3H), 1.5-1.6 (m, 1H), 1.73-1.85 (m 1H), 1.88-1.97 (m, 1H), 2.24-2.35 (m, 1H), 3.60 (d, 1H), 3.76 (dd, 1H).
Reaction SMILES: [Li+].[Cl-].C(COC)OC.Br[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([Mg]Cl)=[CH:20][CH:19]=1>O1CCCC1.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:20][CH:19]=1
Reactant: N#Cc1ccccc1Br
Reactant: Cc1ccc([Mg]Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C

Procedure:
A suspension of MnCl2 (0.25 g, 1.98 mmol) and LiCl (0.17 g, 3.955 mmol) in a mixture of 2 ml of anhydrous tetrahydrofuran and 0.38 ml of dimethoxyethane (3.955 mmol) is stirred at room temperature. After stirring for approximately 30 minutes, a homogeneous medium is obtained. The addition is then so carried out of 1/1: PdCl2/dppp (0.023 g, 1 mol %) and of o-bromobenzonitrile (0.72 g, 3.955 mmol) and then a solution of p-tolylmagnesium chloride in tetrahydrofuran (1.80N, 2.86 ml, 5.14 mmol) is added over 2 hours at room temperature. After stirring for 90 minutes, the reaction mixture is treated as described in Example 1. The o-(p-tolyl)benzonitrile is thus obtained with a yield of isolated product of 95%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[N:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2[OH:19].Br[CH2:21][C:22]([O:24]CC)=[O:23].[OH-].[Na+]>CS(C)=O>[CH3:7][O:8][C:9]1[N:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2[O:19][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2nccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2nccc(OCC(=O)O)c2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
K2CO3 (785 mg, 1 eq.) was added to a suspension of 6-methoxy-[1,5]naphthyridin-4-ol (1 g, 5.7 mmol, WO 02/08224) in DMSO (7 mL). The mixture was vigorously stirred for 2.5 h after which ethyl bromoacetate was added dropwise. The resulting mixture was heated at 50° C. for 4 h. 2N NaOH (5 mL) was then added at 50° C. and stirring was continued at rt overnight. The mixture was quenched with water. AcOH was added and the mixture was extracted with DCM/MeOH 9:1. The org. layer was washed with water, dried over MgSO4 and concentrated to afford the title intermediate as a pale yellow solid (693 mg, 52% yield).