Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13][OH:14])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13][O:14][S:26]([CH3:25])(=[O:28])=[O:27])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1sc2cc(OCCO)ccc2c1-c1ccc(C(F)(F)F)cc1
Product: Cc1sc2cc(OCCOS(C)(=O)=O)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 21.1, 2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethanol and methanesulfonic acid chloride were converted to yield Methanesulfonic acid 2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl ester as colorless solid, MS: 430 (M+).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:45][C:46]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=1[C@@H:53]1[CH2:63][CH2:62][C@H:61](O)[C:56]2=[N:57][CH:58]=[CH:59][CH:60]=[C:55]2[C@H:54]1[NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69]>C(Cl)Cl>[F:45][C:46]1[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=1[C@@H:53]1[CH2:63][CH2:62][C@@H:61]([N:19]2[C:15](=[O:25])[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:20])[C:56]2=[N:57][CH:58]=[CH:59][CH:60]=[C:55]2[C@H:54]1[NH:65][C:66](=[O:72])[O:67][C:68]([CH3:70])([CH3:69])[CH3:71]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@@H](O)CC[C@H]1c1cccc(F)c1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@H](N2C(=O)c3ccccc3C2=O)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 113.7 %

Procedure:
DIAD (0.356 mL, 1.832 mmol) was added to a methylene chloride (5 mL) solution of phthalimide (0.270 g, 1.832 mmol), triphenylphosphine (0.481 g, 1.832 mmol) and tert-butyl (5S,6S,9S)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate (0.358 g, 0.916 mmol) at 0° C. The reaction was gradually warmed up to room temperature and stirred at room temperature for 3 days. Volatile components were removed in vacuo and the crude residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed two more times with water before being dried (sodium sulfate), filtered and concentrated. Flash chromatography using ethyl acetate in hexane from 0 to 45% gave the desired product (0.541 g, ca 80% purity, 90% for 2 steps): MS(ESI)[M+H+]=520.16.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:20])[NH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:21]([O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=1)[CH3:22].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12]([NH:11][C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[O:20])=[CH:27][CH:26]=1)[CH3:22]
Reactant: O=C(O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(COC(=O)CCCNC(=O)NC23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 12 h
Yield: 76.2 %

Procedure:
To a solution of 4-(3-adamantan-1-yl-ureido)butyric acid 822 (1.23 g, 0.83 mmol), DMAP (0.05 g, 0.42 mmol), and the above alcohol (0.15 g, 0.83 mmol) in methylene chloride (30 mL) was added EDCI (0.16 g, 0.83 mmol) at room temperature. After stirring for 12 h, the reaction mixture was washed with 1 N NaOH aqueous solution (15 mL) and water (30 mL), and the organic layer was dried over Na2SO4 and concentrated. Then the residue was purified by column chromatography on silica gel eluting hexane and ethyl acetate (5:1) to provide 849 (0.28 g, 75%) as a white solid: 1H NMR (CDCl3) 1.40 (3H, t, J=6.9 Hz), 1.66-1.68 (6H, m), 1.84 (2H, quint, J=6.9 Hz), 1.94-1.96 (6H, m), 2.05-2.07 (3H, m), 2.44 (2H, t, J=6.9 Hz), 3.17 (2H, q, J=6.9 Hz), 4.02 (1H, s), 4.17 (1H, s), 4.38 (2H, q, J=6.9 Hz), 5.17 (2H, s), 7.40 (2H, d, J=7.8 Hz), 8.00 (2H, d, J=7.8 Hz); LC-MS (ESI) m/z calcd for C25H34N2O5 [M+H]+ 443.25. found [M+H]+ 443.25; mp 96-99 C. Anal. (C25H34N2O5) C, H, N.
Reaction SMILES: [CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].[H][H]>C(O)C.[Ni]>[CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH:20]=2)[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH2:2][CH3:3]
Reactant: C=CCC1(C2=CCN(C)CC2)c2ccccc2CCc2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCCC1(C2=CCN(C)CC2)c2ccccc2CCc2ccccc21
Yield: 50.3 %

Procedure:
Dissolved 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methyl-1,2,5,6-tetrahydropyridine (0.39 g, 1.2 mmol) in 50 mL of absolute ethanol, and added a teaspoon of Raney nickel paste. Hydrogenated on a Paar shaker at 17 psi of hydrogen pressure for 16 hours. Filtered to remove catalyst, and evaporated filtrate to a solid. Recrystallized crude product from hexane to give 0.20 g (50% yield) of 4-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methyl-1,2,5,6-tetrahydropyridine as a white solid.
Reaction SMILES: [ClH:1].[C:2]1([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]4[CH2:20][CH2:21][NH:22][CH2:23][C:13]([C:14]=34)=[CH:12]2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C=O.Cl>C1COCC1>[ClH:1].[CH3:24][N:22]1[CH2:21][CH2:20][C:15]2[C:14]3[C:13](=[CH:12][N:11]([S:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)(=[O:10])=[O:9])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:23]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=S(=O)(c1ccccc1)n1cc2c3c(cccc31)CCNC2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCc2cccc3c2c(cn3S(=O)(=O)c2ccccc2)C1
Temperature: 70 °C
Yield: 12 %

Procedure:
1-(Phenylsulfonyl)-3,4,5,6-tetrahydro-1H-azepino[3,4,5-cd]indole hydrochloride, Example 12 (100 mg, 0.3 mmol) was dissolved in THF (4 mL) before sodium triacetoxyborohydride (203 mg, 1.0 mmol) and acetic acid (191 mg, 3.2 mmol) was added. Aqueous formaline (37%, 1 mL) was added and the reaction mixture was heated in MW at 70° C. for 300 s. The reaction mixture was evaporated and the crude product was purified by preparative HPLC using System B, 100 mM NH4HCO3/MeCN (36-66% MeCN). The product was isolated and transformed to the hydrochloride. 15.2 mg of the pure product was isolated as an yellow oil, yield 12%. MS m/z 327 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH:7]=[O:8].[C:9]1([Li])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8]
Reactant: Cc1ncoc1C=O
Reactant: [Li]c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncoc1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Methyl-5-oxazolecarbaldehyde (600 mg) in dry tetrahydrofuran (10 ml) was added dropwise to a stirred solution of phenyllithium (2.0M solution in cyclohexane and diethyl ether, 2.8 ml) in tetrahydrofuran (20 ml) at -70° C. under an atmosphere of dry nitrogen. After 1 hour the mixture was allowed to warm to room temperature. After a further 1 hour saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The product was purified by flash chromatography to yield the title compound. M.p. 79°-81° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO[C:6]([C:8]1[N:9]=[N:10][N:11]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[C:36]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:35][C:34]=2[O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:12]=1[N:13]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=[O:7]>CO>[C:29]([O:28][C:26](=[O:27])[N:13]([C:12]1[N:11]([C:33]2[CH:38]=[C:37]([CH:39]([CH3:40])[CH3:41])[C:36]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:35][C:34]=2[O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:10]=[N:9][C:8]=1[C:6](=[O:7])[NH:3][CH2:1][CH3:2])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:16][CH:15]=1)([CH3:31])([CH3:30])[CH3:32]
Reactant: COC(=O)c1nnn(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1N(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Reactant: CCN
Solvent: CO
Product: CCNC(=O)c1nnn(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1N(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Temperature: 80 °C

Procedure:
EtNH2 (1.5 ml of a solution 2 M in MeOH) was added to 1-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-5-[tert-butoxycarbonyl-(4-morpholin-4-yl-phenyl)-amino]-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (110 mg, 0.15 mmol) and the mixture was heated to 80° C. for 24 hours in a sealed tube. The solvent and the excess of amine were removed under reduced pressure and the residue was used in the next reaction without any purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH2:14][C:15]3[NH:16][CH:17]=[CH:18][N:19]=3)[CH:12]=[CH:13][C:7]=2[C:6]=1[CH3:20])=[O:4].[OH-].[K+].O>CO>[NH:19]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:14][C:11]1[CH:12]=[CH:13][C:7]2[C:6]([CH3:20])=[C:5]([C:3]([OH:4])=[O:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1sc2cc(Cc3ncc[nH]3)ccc2c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)sc2cc(Cc3ncc[nH]3)ccc12
Yield: 84.1 %

Procedure:
A mixture of 6-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (0.25 g.) potassium hydroxide (0.10 g.), water (2.5 ml.) and methanol (2.5 ml.) was heated under reflux for 1 hour and then evaporated to small bulk. The solution was acidified with acetic acid and the solid was filtered off and dissolved in a slight excess of diluted potassium hydroxide solution. The solution was filtered and the filtrate was acidified. The solid was filtered off, washed with water and dried to give 6-(1-imidazolylmethyl)-3-methylbenzo[b]-thiophene-2-carboxylic acid (0.20 g.), m.p. 277°-278° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[C:9]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([NH2:1])[C:5]=3[CH:6]=[CH:7][N:8]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cccc2c(Nc3ccc(C(F)(F)F)cc3)nccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c(Nc3ccc(C(F)(F)F)cc3)nccc12
Yield: 38.1 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-1, step-3 using 5-nitro-N-(4-(trifluoromethyl)phenyl)isoquinolin-1-amine (750 mg, 2.25 mmol), iron powder (1.26 g, 22.5 mmol), and NH4Cl (963 mg, 18.0 mmol) in EtOH—H2O (5:2, 7 mL) to afford 260 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.27 (s, 1H), 8.09 (d, J=9.0 Hz, 2H), 7.94 (d, J=6.0 Hz, 1H), 7.64 (m, 3H), 7.44 (d, J=5.7 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 5.87 (br s, 2H); MS (m/z): 304.28 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH:10]([OH:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1oc2ccccc2c1C(O)c1ccc(O)cc1
Temperature: -10 °C

Procedure:
A solution containing commercial 2-n-butyl-3-(4-hydroxybenzoyl)benzofuran (0.500 g, 17.0 mmol) and lithium aluminum hydride (34.0 mmol) in THF (84 mL) was refluxed for 3 h. The reaction was cooled to −10° C., and carefully quenched with 0.1N NaOH and H2O. The aqueous solution was extracted with ether and concentrated. Purification on silica gel gave the title compound as a white solid, mp 94-96° C. (DMSO-d6) δ0.90 (t, 3H), 1.35 (sextet, 2H), 1.64 (quintet, 2H), 2.84 (t, 2H), 5.67 (d, 1H), 5.87 (d, 1H), 6.69 (d, 2H), 7.07 (t, 1H), 7.15 (dt, 1H), 7.22 (d, 2H), 7.40-7.43 (m, 2H), 9.24 (s, 1H). IR (KBr) 3350, 2950, 1610, 1510 and 1450 cm−1. mass spectrum (EI) m/z 296 (M+). Anal. Calcd. for C19H20O3: C, 77.00; H, 6.80; N, 0.00. Found: C, 75.63; H, 6.86; N, 0.04.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])=[CH:9][CH:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(O)cc3)c(Cl)cc2F)c1=O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)cc1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
0.43 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (produced in Intermediate Production Example 1) was dissolved in 2.0 ml of N,N-dimethylformamide, and to this was added 0.15 g of anhydrous potassium carbonate, and 0.17 g of methyl 2-bromopropionate was added with stirring at room temperature, then, the mixtures was stirred for 3 hours at 70° C. The reaction solution was cooled to room temperature, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residues was subjected to silica gel column chromatography to obtain 0.39 g of methyl 2-[4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [Compound 1-1 of the present invention].
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:9]=[C:8]([CH3:18])[C:5]=1[C:6]#[N:7])[CH3:2].N.S(=O)(=O)(O)[OH:21]>O>[CH2:1]([S:3][C:4]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH:9]=[C:8]([CH3:18])[C:5]=1[C:6]([NH2:7])=[O:21])[CH3:2]
Reactant: CCSc1cc(N2CCOCC2)cc(C)c1C#N
Reactant: O=S(=O)(O)O
Agent: N
Solvent: O
Product: CCSc1cc(N2CCOCC2)cc(C)c1C(N)=O

Procedure:
A solution of 2-ethylsulfanyl-6-methyl-4-morpholin-4-yl-benzonitrile (0.30 g, 1.14 mmol) in concentrated sulfuric acid (15 ml) is stirred at 100° C. for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture is diluted with water (30 ml), basified with aqueous ammonia, and extracted with ethyl acetate (3×15 ml). The organic layer is washed with water (20 ml), brine (15 ml), dried over anhydrous sodium sulfate and evaporated to get 2-ethylsulfanyl-6-methyl-4-morpholin-4-yl-benzamide, which is used in the next step without further purification (0.26 g, 0.92 mmol, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Br[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Oc1ccc(Br)c(OCCN2CCCCC2)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCCC2)cc1OCCN1CCCCC1

Procedure:
4-Bromo-3-(2-{piperidin-1-yl}ethoxy)phenol (1.5 g), bromocyclopentane (0.59 ml) and anhydrous potassium carbonate (1.04 g) were stirred and heated at 80° C. in dimethylformamide for 18 h. The mixture was partitioned between ethyl acetate (100 ml) and water (70 ml). The aqueous was extracted further with ethyl acetate (100 ml) and the combined organics were washed with 2N sodium hydroxide solution (50 ml), water (50 ml), brine (50 ml), dried (MgSO4) and evaporated to give the product as an oil (1.5 g).
Reaction SMILES: [C:1]1([CH3:38])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([CH:30]([CH3:37])[CH2:31][C:32]([O:34]CC)=[O:33])=[C:25]4[C:29]=3[CH2:28][CH2:27][CH2:26]4)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1.[OH-].[Na+]>C(O)C>[C:1]1([CH3:38])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([CH:30]([CH3:37])[CH2:31][C:32]([OH:34])=[O:33])=[C:25]4[C:29]=3[CH2:28][CH2:27][CH2:26]4)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: CCOC(=O)CC(C)c1ccc(NC(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)c2c1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C(C)CC(=O)O)c4c3CCC4)cc2o1
Reaction time: 48 h
Yield: 55.6 %

Procedure:
A solution of ethyl 3-{7-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-indan-4-yl}-butanoat [0.754 g, Reference Example 1(a)] in ethanol (150 mL) was treated with aqueous sodium hydroxide solution (4 mL, 1M). The reaction mixture was allowed to stand at room temperature for 48 hours, then heated at reflux temperature for 1 hour and then evaporated. The residue was dissolved in a mixture of acetonitrile and water (35:65, v/v) and the resulting solution was acidified to pH 2 by addition of trifluoroacetic acid. The resulting solid was filtered and subjected to reversed phase HPLC (Hypersil Elite C18 column, 10×2 cm, using acetonitrile and water mixtures containing 0.1% trifluoroacetic acid and running a linear gradient of +1% acetonitrile/minute, starting with 35% acetonitrile) to give the title compound (396 mg) as a white solid. LC-MS: RT=3.37 minutes (>98% by ELSD); MS(ES+), 484(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccnc(Br)c1
Product: O=C(Nc1ccccc1)c1ccnc(Br)c1

Procedure:
In a manner similar to that described in Preparation 17, 2-bromoisonicotinic acid and aniline were converted to the title compound
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[C:23]1([CH2:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[O:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)Cc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Cc1ccccc1)c1ccc(OC[C@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.9 %

Procedure:
To the product from step 1 (51 mg, 0.129 mmol) was added 4M HCl in dioxane (6 mL) and the resulting mixture was stirred at rt for 3 h. The solvent was removed in vacuo to obtain the title product as a yellow solid (43 mg, 99%): MS; m/z 296 (M+H): LCMS (UV) 99%. 1H NMR (400 MHz, DMSO-d6) δ 1.72-1.77 (m, 1H), 1.87-2.01 (m, 2H), 2.11-2.15 (m, 1H), 3.21-3.23 (m, 2H), 3.91-3.93 (m, 1H), 4.22-4.27 (dd, 1H J1=8, J2=10.8 Hz), 4.33-4.37 (dd, 1H J1=4 Hz, J2=10.8 Hz), 4.33 (s, 2H), 7.09 (d, 2H, J=9.2 Hz), 7.20-7.33 (m, 4H); 8.05 (d, 2H, J=9.2 Hz), 9.1 (s, 1H), 9.6 (s, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:28]2
Reactant: COc1cccc2c1CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1cccc2c1CN(c1c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 61.1 %

Procedure:
4.16 g of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 2.5 g of 4-methoxyisoindoline, 6.4 g of DBU, and 28 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 3.64 g of the target compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:15]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])([F:17])[F:16])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH:12]([OH:14])[CH3:13])[CH:6]=2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[C:12]([C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([Br:1])[C:3]([C:15]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])([F:16])[F:17])=[CH:4]2)=[CH:9][CH:8]=1)(=[O:14])[CH3:13]
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2cc(C(C)O)ccc2cc1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CCOP(=O)(OCC)C(F)(F)c1cc2cc(C(C)=O)ccc2cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl [3-bromo-7-(1-hydroxyethyl)-2-naphthyl](difluoro)methylphosphonate (20 mg) from step 1, in CH12Cl2 (2 mL) at 0° C. was added Dess-Martin reagent (24 mg). The temperature was raised to rt and the reaction stirred for 1 h. The reaction was filtered on a pad of SiO2 eluting with 30% EtOAc/hexanes and the organics were evaporated to dryness. The residue was dissolved and hydrolysed with neat TMSBr (3 mL) and stirred at rt. overnight. The mixture was evaporated to dryness and the residue was dissolved in ethanol. It was evaporated to dryness again and the process was repeated 3 times. The reaction residue was dissolved in water, co-distilled with toluene and pumped with high vacuum to afford the titled product. 1H NMR (500 MHz, CD3OD): δ 8.79 (d, 1H), 8.50 (s, 1H), 8.39 (s, 1H), 8.15 (d, 1H), 8.02 (d 1H), 2.75 (s, 3H).
Reaction SMILES: [C:1]1([P:7](Cl)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:20]=[N+:21]=[N-:22])(C)C>>[C:1]1([P:7]([N:20]=[N+:21]=[N-:22])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Product: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Following a previously [Paciorek et al, Inorg. Nucl. Chem. Letters, 2, 39 (1966)] developed procedure, diphenylphosphinyl chloride (14.87 g, 62.86 mmol) was introduced into a tube (in the inert atmosphere enclosure). Trimethylsilyl azide (10.45 g, 90.69 mmol) was then condensed onto this material on a vacuum line at liquid nitrogen temperature. The tube was sealed in vacuo and heated at 60° C. for 48 hr. Thereafter, it was cooled, opened to a vacuum system and the volatiles were collected in a liquid nitrogen trap (originally without pumping at room temperature, finally with pumping at 70° C.). The total time required to remove the volatiles (excess (CH3)3SiN3 and the by-product (CH3)3SiCl) was 16 hr. A quantitative yield of pure diphenylphosphinyl azide was realized.