Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]23[CH2:16][N:12]([CH2:13][CH2:14][CH2:15]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:2]2[N:7]=[CH:6][C:5]([C:8]34[CH2:16][N:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11][CH2:10][CH2:9]4)=[CH:4][CH:3]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: Clc1ccc(C23CCCN(CCC2)C3)cn1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccc(C34CCCN(CCC3)C4)cn2)cc1OC
Temperature: 110 °C

Procedure:
0.055 g (0.23 mmol) of 5-(6-chloropyridin-3-yl)-1-azabicyclo[3.3.1]nonane obtained in Example 2, in solution in 12 ml of a 1,2-dimethoxyethane/water 8/4 mixture, is introduced into a 100 ml round-bottomed flask. 0.106 g (0.58 mmol) of 3,4-dimethoxyphenylboronic acid, 0.08 g (0.58 mmol) of potassium carbonate and 0.024 g (0.03 mmol) of dichlorobis(triphenylphosphine)palladium(II) are then successively introduced under an argon atmosphere. The mixture is heated at 110° C. for 2 hours, cooled to ambient temperature and poured into 300 ml of a saturated aqueous sodium carbonate solution. The aqueous phase is extracted twice with 100 ml of chloroform, and the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of chloroform, methanol and aqueous ammonia in the proportions 90/10/1. The compound obtained in the base form (5-[6-(3,4-dimethoxyphenyl)pyridin-3-yl]-1-azabicyclo[3.3.1]nonane) is converted to the hydrochloride by adding two equivalents of hydrochloric acid in solution (5-6 N) in isopropyl alcohol. After triturating from diethyl ether, 0.035 g of the expected product is obtained in the form of a yellow powder.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C:17](=[O:18])[N:16]2[C@@H:12]1[C@@H:13]([CH3:27])[C:14]([S:25][CH3:26])=[C:15]2[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH3:10])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]([C@H:11]1[C:17](=[O:18])[N:16]2[C@@H:12]1[C@@H:13]([CH3:27])[C:14]([S:25][CH3:26])=[C:15]2[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH3:10]
Reactant: C=CCOC(=O)C1=C(SC)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C=CCOC(=O)C1=C(SC)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 24 h
Yield: 80.8 %

Procedure:
Allyl (4R,5S,6S)-6-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-3-methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (100 mg) was added to a mixture of 70% aqueous tetrabutylammonium fluoride (0.71 g) and acetic acid (121 mg) in tetrahydrofuran (2 ml) and the mixture was allowed to stand at ambient temperature for 24 hours. The solution was diluted with ethyl acetate (6 ml), washed with water, aqueous sodium bicarbonate solution and brine, and dried. The solvent was removed off under reduced pressure and the residue was crystallized from n-hexane to afford allyl (4R,5S,6S)-6-((1R)-1-hydroxyethyl)-4-methyl-3-methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (58.4 mg).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[Si](N=C=O)(N=C=O)(N=C=O)[N:18]=[C:19]=[O:20]>C1C=CC=CC=1>[CH3:1][N:2]([CH:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[O:10][C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:19]([NH2:18])=[O:20]
Reactant: CNC1c2ccccc2Oc2ccccc21
Reactant: O=C=N[Si](N=C=O)(N=C=O)N=C=O
Solvent: c1ccccc1
Product: CN(C(N)=O)C1c2ccccc2Oc2ccccc21

Procedure:
A solution of 9-methylaminoxanthen (5 g.) in dry benzene (10 ml.) was added slowly to a stirred solution of silicon tetraisocyanate (1.16 g.) in benzene (10 ml.). The resulting solution was refluxed for 45 minutes and then evaporated to dryness in vacuo. The residue was refluxed for 30 minutes with 90% isopropanol (20ml.), filtered and the filtrate evaporated to dryness. The residue was washed with cold acetone and recrystallised from ethanol to give N-methyl-N-9-xanthenylurea, m.p. 199°-202°C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH3:13])[NH:8][C:7]=2[C:6](=S)[NH:5][C:4]1=[S:15])[CH3:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CC(C)=O>[CH2:1]([N:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH3:13])[NH:8][C:7]=2[C:6]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][C:4]1=[S:15])[CH3:2]
Reactant: CCc1nc2c([nH]1)c(=S)[nH]c(=S)n2CC
Reactant: C1COCCN1
Solvent: CC(C)=O
Product: CCc1nc2c([nH]1)c(N1CCOCC1)nc(=S)n2CC
Temperature: 25 °C

Procedure:
The product of stage (i) (14.42 g) was refluxed in 78.4 ml (900 mmoles) of morpholine for 30 hours. After cooling to room temperature the reaction product was suspended in 100 ml of acetone and the title product (16.49 g) collected and washed.
Reaction SMILES: C1C2C(=CC(CNC)=CC=2)CC1.[CH3:13][NH:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=C[CH:20]=[CH:21][CH:22]=2)[C:17]=1CCC.Cl.[O:30]=[C:31]1[NH:40][C:39]2[N:38]=[CH:37][C:36](/[CH:41]=[CH:42]/[C:43](O)=[O:44])=[CH:35][C:34]=2[CH2:33][CH2:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH2:22]1[C:23]2[C:24](=[CH:25][C:16]([CH2:15][N:14]([CH3:13])[C:43](=[O:44])/[CH:42]=[CH:41]/[C:36]3[CH:37]=[N:38][C:39]4[NH:40][C:31](=[O:30])[CH2:32][CH2:33][C:34]=4[CH:35]=3)=[CH:17][CH:18]=2)[CH2:20][CH2:21]1
Reactant: CCCc1c(CNC)ccc2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CNCc1ccc2c(c1)CCC2
Agent: Cl
Product: CN(Cc1ccc2c(c1)CCC2)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 45 %

Procedure:
According to the procedure of Example 1 (a), except substituting indan-5-ylmethyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.232 g, 45%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.66-10.64 (m, 1H), 8.36-8.33 (m, 1H), 8.07-8.06 (m, 1H), 7.54-7.49 (m, 1H), 7.33-6.89 (m, 4H), 4.75-4.56 (m, 2H), 3.07-2.72 (m, 9H), 2.53-2.49 (m, 2H), 2.04-1.94 (m 2H); MS (APCI) m/e 362 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:41][CH3:42])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)=[O:12])=[C:6]([C:22]2[CH:27]=[C:26]([C:28](=[O:40])[NH:29][C@@H:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][CH2:32][CH2:31]3)[CH:25]=[CH:24][N:23]=2)[CH:5]=1)[CH3:2].[CH3:43][NH:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH2:41]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([N:44]([CH3:43])[CH2:45][CH2:46][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[O:18])[CH:14]=2)=[C:6]([C:22]2[CH:27]=[C:26]([C:28](=[O:40])[NH:29][C@@H:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][CH2:32][CH2:31]3)[CH:25]=[CH:24][N:23]=2)[CH:5]=1)[CH3:42]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)O)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: CNCCN1CCOCC1
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a mixture of (S)-3-((4-(diethylamino)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzoic acid (1.81 mmol, 1.15 g), N-methyl-2-morpholinoethanamine (2.17 mmol, 0.313 g) and DIEA (12.67 mmol, 1.64 g) in DMF (5 mL) was added HATU (2.17 mmol, 0.826 g), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (1×), dried and concentrated. The residue was purified by column to give a yellow solid (0.98 g, 79%). MS (ESI, m/z) 689.28 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=2[F:20])[CH2:7][CH2:6]1)=[O:4].[Cl:21][C:22]1[CH:31]=[CH:30][C:25]2[NH:26][C:27](=[O:29])[O:28][C:24]=2[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=4[F:20])[CH2:7][CH2:6]3)=[O:4])[C:27](=[O:29])[O:28][C:24]=2[CH:23]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)c(F)cc1Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(Cl)ccc43)CC2)c(F)cc1Cl

Procedure:
Compound 5 was prepared according to the procedure described in Example 2 using 2-chloro-1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-piperazin-1-yl]-ethanone (4), 6-chloro-3H-benzooxazol-2-one and K2CO3 in DMF: HPLC retention time, 2.70 minutes, (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 454.3, found, 454.4.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=1)=O)(C)(C)C.[ClH:25].CCOC(C)=O>CCOC(C)=O>[ClH:25].[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=1
Reactant: CCOC(=O)COc1ccc(CCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(CCCN)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl (4-{3-[(tert-butoxycarbonyl)amino]propyl}phenoxy)acetate (2.5 g) in EtOAc (7.5 mL) was added 4 M HCl/EtOAc (10 mL) at ambient temperature. After stirring for 5 hours at ambient temperature, the mixture was evaporated in vacuo to give a ethyl [4-(3-aminopropyl)phenoxy]acetate hydrochloride.
Reaction SMILES: O.[OH-].[Li+].O.[CH3:5][O:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:26]([O:28]C)=[O:27])=[CH:12][N:13]2[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1.Cl>O1CCCC1>[C:26]([C:11]1[C:10]2[C:14](=[CH:15][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)[N:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH:12]=1)([OH:28])=[O:27]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)c2cc(OC)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(C(=O)O)cn(-c3ccnc4ccccc34)c2c1
Reaction time: 19 h

Procedure:
0.947 g (22.57 mmol) of lithium hydroxide monohydrate and 115 cm3 of water are added at a temperature in the region of 25° C. to 2.5 g (7.52 mmol) of 6-methoxy-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole dissolved in 115 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 19 hours, the reaction mixture is concentrated under reduced pressure (2.7 kPa) to give a residue which is taken up with 22.5 cm3 of N hydrochloric acid. After filtering off and drying the solid residue at atmospheric pressure at a temperature in the region of 60° C., 2.4 g of 3-carboxy-6-methoxy-1-(quinol-4-yl)-1H-indole are obtained in the form of a beige-coloured solid which decomposes at approximately 175° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]1[C:34](=[O:35])[N:15]2[C:16]([C:23]([O:25][CH:26]([O:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:27])=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]12.[CH:36]([NH:38][C:39]1[S:40][CH:41]=[C:42]([C:44](=[O:48])[C:45](O)=[O:46])[N:43]=1)=[O:37]>>[CH:36]([NH:38][C:39]1[S:40][CH:41]=[C:42]([C:44](=[O:48])[C:45]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:23]([O:25][CH:26]([O:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:27])=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:46])[N:43]=1)=[O:37]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: CCOC(=O)OC(C)OC(=O)C1=C(COC)CS[C@@H]2C(N)C(=O)N12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)OC(C)OC(=O)C1=C(COC)CS[C@@H]2C(NC(=O)C(=O)c3csc(NC=O)n3)C(=O)N12
Yield: 52.6 %

Procedure:
The procedure described in Preparation 21 was repeated, but using 2.8 g of 1-ethoxycarbonyloxyethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate p-toluenesulphonate and 1.25 g of 2-(2-formamidothiazol-4-yl)glyoxylic acid, to give 1.5 g of the title compound.
Reaction SMILES: [OH:1][C@:2]([CH3:18])([CH2:16][OH:17])[CH2:3][CH2:4][C:5]1[C:6](=[O:15])[C:7]([CH3:14])=[C:8]([CH3:13])[C:9](=[O:12])[C:10]=1[CH3:11].[H][H].C>C(OCC)(=O)C.[Pd]>[OH:1][C@:2]([CH3:18])([CH2:16][OH:17])[CH2:3][CH2:4][C:5]1[C:6]([OH:15])=[C:7]([CH3:14])[C:8]([CH3:13])=[C:9]([C:10]=1[CH3:11])[OH:12]
Reactant: [H][H]
Reactant: CC1=C(C)C(=O)C(CC[C@](C)(O)CO)=C(C)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(C)c(O)c(CC[C@](C)(O)CO)c(C)c1O
Yield: 100.8 %

Procedure:
A solution of 0.405 g (1.6 mmoles) of (S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethyl-p-benzoquinone in 20 ml of ethyl acetate was stirred in an atmosphere of hydrogen, in the presence of 0.04 g of 5% by weight palladium on 95% by weight charcoal until H2 uptake ceased (ca. 1 hr; 38 ml H2 absorbed). The catalyst was filtered and the filtrate was concentrated giving 0.41 g of (S)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethylhydroquinone as a tan solid, mp 124°-131.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]3[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([S:29]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[OH:35][CH2:34][C:33]([NH:32][S:29]([C:25]1[CH:24]=[C:23]([NH:22][C:19]([C:18]2[CH:17]=[N:16][N:11]3[C:12]([CH2:14][CH3:15])=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:20])[CH:28]=[CH:27][CH:26]=1)(=[O:31])=[O:30])([CH3:37])[CH3:36]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: CCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Product: CCc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)Nc3cccc(S(=O)(=O)NC(C)(C)CO)c3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-ethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.26) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Pale-yellow solid. MS (ISP) 528.0 [(M+H)+]; mp 239-240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:5]=[N:6][C:7]=1Cl.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][O:24][C:23]2=[O:32])[CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:5]=[N:6][C:7]=1[N:16]1[CH2:17][CH2:18][CH:19]([N:22]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:25][O:24][C:23]2=[O:32])[CH2:20][CH2:21]1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: CC(C)NC(=O)c1cnc(Cl)c(Cl)c1
Agent: Cl
Product: CC(C)NC(=O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1

Procedure:
The title compound was prepared from the product of step (i) (0.3 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.35 g) using the method of example 115 step (ii). Yield 0.187 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[C:10]([OH:11])=[CH:9][C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24]>CN(C)C=O.O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[C:10]([O:11][CH2:23][CH3:24])=[CH:9][C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(C(C)(C)C)cc1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
6-tert-Butyl-4-hydroxy-nicotinic acid ethyl ester (110 mg, 0.5 mmol) was dissolved in dimethylformamide (6 mL). Potassium carbonate was added followed by dropwise addition of ethyl iodine (0.13 mL, 1.5 mmol). The reaction mixture was stirred at room temperature overnight. It was diluted with water and brine and extracted with diethyl ether (2×30 mL). Combined organics washed with brine/water, dried and concentrated to give 6-tert-butyl-4-ethoxy-nicotinic acid ethyl ester as viscous oil (100 mg, 80%). LR-MS: 251 [(M+H)+]
Reaction SMILES: [C:1]([NH:4][C:5]([CH3:12])([CH:9]([CH3:11])[CH3:10])[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(OC(Cl)=O)C.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:24][CH:25]=1.[Na]>C(N(CC)CC)C.C(OCC)C.CN(C)C=O>[C:1]([NH:4][C:5]([CH3:12])([CH:9]([CH3:11])[CH3:10])[C:6]([NH:29][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:27])=[O:28])=[O:8])(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)NC(C)(C(=O)O)C(C)C
Agent: CCOC(=O)Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)NC(C)(C(=O)NS(=O)(=O)c1ccc(C)cc1)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 116.7 %

Procedure:
2-Acetamido-2,3-dimethylbutyric acid (1.5 g) is dissolved in a solution of triethylamine (2.7 g) in diethyl ether (50 mL) and cooled to 0° C.; ethylchloroformate (1.1 g) is added dropwise and the mixture is stirred at 0° to room temperature over one hour. The mixture is filtered, and the filtrate is concentrated in vacuo to afford the oily mixed anhydride (1.5 g). This material is mixed with 3 g of p-toluenesulfonamide, sodium salt, in 25 mL dimethylformamide, and the resulting mixture is heated at 80° C. for 16 hours. The reaction is cooled, concentrated in vacuo, and the residue is partitioned between methylene chloride and saturated, aqueous sodium bicarbonate. Acidification of the aqueous layer with conc. HCl to pH 1, extraction with CH2Cl2, drying, and stripping the organic phase affords the title product (3.3 g).
Reaction SMILES: ClCCl.[NH2:4][CH2:5][C:6]([CH3:9])([OH:8])[CH3:7].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>C(N(CC)CC)C>[CH3:7][C:6]([OH:8])([CH3:9])[CH2:5][NH:4][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
To a stirred solution of 150 mL of dichloromethane, 10 mL of triethylamine and 6.7 g (0.075 mole) of 1-amino-2-methyl-2-propanol was added 10.4 g (0.05 mole) of 4-chloro-3-nitroquinoline. The solution was heated on a steam bath for about one hour then evaporated to remove the solvent. The residue was dissolved in dilute hydrochloric acid and filtered. The filtrate was made basic with concentrated ammonium hydroxide to reprecipitate the product. The product was separated by filtration and recrystallized twice from ethanol to provide the novel yellow solid 2-methyl-1-[(3-nitro-4-quinolinyl)amino]-2-propanol, m.p. 244°-246° C. (dec.). Analysis: Calculated for C13H15N3O3 : %C, 59.8; %H, 5.8; %N, 16.0; Found: %C, 59.8; %H, 5.9; %N 16.1.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22]C(=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:29][CH2:30][CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C:33]1=[O:41].ClCCl>CO.O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:29][CH2:30][CH2:31][N:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:34][C:33]3=[O:41])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=C1Cc2ccccc2N1CCCCl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCN3C(=O)Cc4ccccc43)c2CC1
Temperature: 25 °C

Procedure:
Add potassium hydroxide (899 mg, 16.64 mmol) in one portion to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.52 mmol) in methanol (10 mL). Heat the reaction to 50° C. under nitrogen for 24 h, then cool to room temperature and add 1-(3-chloro-propyl)-1,3-dihydro-indol-2-one (217 mg, 1.04 mmol). Stir the reaction at room temperature for 4 days. Remove solvents in vacuo, add dichloromethane (20 mL) and water (20 mL). Remove the organic layer and dry using an ISCO® phase separator then concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-indol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as orange powder. MS (ES+) m/z: 509 (M+Na)+.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([C:26]2[O:30][N:29]=[CH:28][C:27]=2[CH2:31][CH2:32][C:33](O)=[O:34])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([C:33](=[O:34])[CH2:32][CH2:31][C:27]3[CH:28]=[N:29][O:30][C:26]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1cnoc1-c1ccccc1)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A mixture of N-diphenylmethylpiperazine (0.85 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.55 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-diphenylmethyl-N′-[3-(5-phenyl-4-isoxazolyl)propionyl]piperazine (1.35 g, yield 93%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl3) δ: 2.26–2.42 (4H, m), 2.50–2.64 (2H, m), 2.94–3.08 (2H, m), 3.32–3.44 (2H, m), 3.56–3.68 (2H, m), 4.22 (1H, s), 7.12–7.54 (13H, m), 7.66–7.86 (2H, m), 8.21 (1H, s).