Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[O:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[C@H:18]3[CH2:19][N:20]([C:22](OCC)=O)[CH2:21][C@@H:17]3[C:16]=2[CH:34]=1.[OH-].[Na+]>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[O:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[C@H:18]3[CH2:19][N:20]([CH3:22])[CH2:21][C@@H:17]3[C:16]=2[CH:34]=1
Reactant: CCOC(=O)N1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@H]2C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1C[C@@H]2c3ccccc3Oc3ccc(Cl)cc3[C@H]2C1
Temperature: -10 °C
Yield: 72.9 %

Procedure:
Aluminium trichloride (4.1 g, 30.8 mmol, 2 eq.) was added to THF (20 ml) at 0° C. while stirring under inert nitrogen atmosphere and cooling with an ice bath. LiAlH4 (3.6 g, 94.7 mmol, 6 eq.) was then added portionwise while stirring over 15 minutes. After the addition was complete the resulting grey mixture was stirred for 15 minutes at −10° C., while cooling with an ice-acetone bath. Additional THF (10 ml) was added. Then a solution of trans-5-chloro-2,3,3a,12b-tetrahydro-2-ethoxycarbonyl-1H-dibenz[2,3:6,7]-oxepino[4,5-c]pyrrole (Example 18; 5.4 g, 15.7 mmol) in THF (20 ml) was added dropwise over 15 minutes to the in situ prepared alane reagent while stirring and cooling at −10° C. After the addition was complete the reaction mixture was stirred for an additional hour at −10° C. and then for 30 minutes while warming to room temperature. The resulting reaction mixture was carefully poured out in portions to dilute aqueous NaOH (75 ml 30% NaOH and 175 ml water) in a 1000 ml Erlenmeyer flask. After 15 minutes stirring the mixture was extracted with toluene (3×150 ml). The combined organic layers were dried with Na2SO4. Evaporation under vacuum gave crude trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]-oxepino[4,5-c]pyrrole (asenapine) (3.26 g, 11.44 mmol) in 73% c.y. as a brown oil. According to LC-MS ca. 60% pure. MS: M+1=286, 288 found. 1H-NMR (CDCl3) δ (ppm) identical data as above.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[CH3:15][C:16]1[CH:17]=[C:18]([CH:30]([NH2:32])[CH3:31])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:32]([CH:30]([C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[C:16]([CH3:15])[CH:17]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)C(F)F
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)C(F)F
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield (152 mg, yellow oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (172 mg, 0.57 mmol, Amine-17, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([N:11]([CH3:38])[CH2:12][CH2:13][C:14]([O:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[CH:19]([C:20](=O)[CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@H:23]3[CH2:24][CH2:25][C:26]2=[O:36])[CH2:18]1)=[O:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[NH2:40][OH:41]>>[C:1]([N:11]([CH2:12][CH2:13][C:14]([O:16][C@H:17]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[CH:19](/[C:20](=[N:40]/[OH:41])/[CH2:21][C@@H:22]3[C@@H:31]2[CH2:30][CH2:29][C@@:27]2([CH3:28])[C@H:23]3[CH2:24][CH2:25][C:26]2=[O:36])[CH2:18]1)=[O:15])[CH3:38])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: CN(CCC(=O)O[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12)C(=O)OCc1ccccc1
Agent: Cl
Product: CN(CCC(=O)O[C@H]1CC[C@@]2(C)C(C1)/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12)C(=O)OCc1ccccc1
Yield: 60 %

Procedure:
The procedure described in Prepn. 20 was followed starting from 3β-(N-carbobenzyloxy-N-methyl-3-aminopropionyloxy)androstane-6,17-dione (0.70 g) and hydroxylamine hydrochloride. The residue was purified by flash chromatography (SiO2, n-hexane/acetone 60/40) to give the title compound (0.43 g, 60%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.31 (1H, s), 7.30 (5H, m), 5.05 (2H, s), 4.56 (1H, m), 3.50-0.87 (27H, m), 0.78 (3H, s), 0.68 (3H, s).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2([CH2:14][CH2:13][C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)([N:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)[CH2:6][CH2:5]1)C=C.CN(C)C1(C2C=CC=CC=2)CCC2(CCNCC2)CC1>>[F:24][C:20]1[CH:19]=[C:18]([C:12]2([N:15]([CH3:17])[CH3:16])[CH2:11][CH2:10][C:7]3([CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)[CH2:14][CH2:13]2)[CH:23]=[CH:22][CH:21]=1
Reactant: C=CCN1CCC2(CC1)CCC(c1cccc(F)c1)(N(C)C)CC2
Agent: CN(C)C1(c2ccccc2)CCC2(CCNCC2)CC1
Product: CN(C)C1(c2cccc(F)c2)CCC2(CCNCC2)CC1

Procedure:
The reaction was performed starting from 3-allyl-9-(3-fluorophenyl)-N,N-dimethyl-3-azaspiro[5.5]undecan-9-amine in an analogous manner to stage 9 amine (A1). Yield: quantitative
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:11](Cl)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[N:19][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[O:3][C:4]([C:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][CH:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)=[N:19][CH:20]=2)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: O=C(Cl)c1oc(Br)nc1C(F)(F)F
Reactant: Nc1ccc(N2CCC(c3ccccc3)CC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCC(c3ccccc3)CC2)nc1)c1oc(Br)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
A solution of 2-bromo-4-trifluoromethyloxazole-5-carbonyl chloride (A-39) (0.34 g, 1.2 mmol) and 1-(5-aminopyridin-2-yl)-4-phenylpiperidine (B-6) (0.25 g, 1.0 mmol) in CH2Cl2 (10 mL) was cooled to −78° C. then triethyl amine (0.16 mL, 1.2 mmol) was added. The reaction mixture was stirred for 2 h while the temperature was warmed slowly up to 0° C. The solvent was concentrated, and the residue was purified by chromatography on a silica-gel column (eluant: 0-50% EtOAc/hexane gradient) to yield 1-(5-(2-bromo-4-(trifluoromethyl)oxazole-5-carboxamido)pyridin-2-yl)-4-phenylpiperidine (A-40) (0.19 g, 35% yield) as a yellow solid. Note: the product A-40 contains compound with the bromine atom exchanged for a chlorine atom. 1H NMR (500 MHz, CDCl3) δ 9.58 (br s, 1H), 8.59 (br s, 1H), 8.34 (dd, 1H, J=9.5, 1.8 Hz), 7.35 (m, 2H), 7.30-7.22 (m, 3H), 6.89 (d, 1H, J=9.4 Hz), 4.42 (d, 2H, J=13.3 Hz), 3.17 (t, 2H, J=12.7 Hz), 2.85 (m, 1H), 2.05 (m, 2H), 1.84 (m, 2H); LCMS (ESI) calcd for [M+1]+ for chloride 451.1. found 451.4.
Reaction SMILES: C([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=O.[C:23](O)(=O)[CH2:24][C:25]([OH:27])=[O:26].N1CCCCC1>N1C=CC=CC=1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([O:7][C:6]2[CH:21]=[CH:22][C:3]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)O)cc2)CC1

Procedure:
A solution of t-Butyl 4-(4-formyl phenoxy)piperidine-1-carboxylate (50.2 grams, 0.164 moles, obtained in above step), malonic acid (50.6 grams, 0.486 moles) and piperidine (12.5 mL) in pyridine (250 mL) was stirred for 8 hours at 110° C. under nitrogen atmosphere.
Reaction SMILES: [C:1]1([CH:7]([N:14]=[C:15]=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@@:17]12([OH:26])[N:24]([CH3:25])[C@@H:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]=[CH:18]2>C(#N)C>[CH:7]([NH:14][C:15]([O:26][C@@:17]12[N:24]([CH3:25])[C@@H:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]=[CH:18]2)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Solvent: CC#N
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)NC(c1ccccc1)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.5 g (0.012 mol) of diphenylmethylisocyanate is placed in 7 mL acetonitrile, a solution of 1.67 g (0.012 mol) of tropenol in 5 mL acetonitrile is added dropwise. The solution is stirred for 24 hours at ambient temperature; after 10 minutes, a white precipitate is formed. After the end of the reaction time, the suspension is cooled and the precipitate is suction filtered. Yield: 2.28 g (55% of theory); melting point: 140° C.-142° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[N:26]=[C:25]3[C:21]([N:22]=[CH:23][N:24]3[C@@H:27]3[CH2:31][C@H:30]([N:32]4[CH:36]=[C:35]([CH2:37][OH:38])[CH:34]=[N:33]4)[C@@H:29]([OH:39])[C@H:28]3[OH:40])=[C:20]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:19]=2)=[O:17])[CH2:11][CH2:10]1.FC(F)(F)C(O)=O.O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(N[C:108]([NH:110][CH:111]3[CH2:116][CH2:115][N:114]([C:117]4[CH:122]=[CH:121][CH:120]=[CH:119][N:118]=4)[CH2:113][CH2:112]3)=[O:109])CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:114]1([C:117]2[CH:122]=[CH:121][CH:120]=[CH:119][N:118]=2)[CH2:115][CH2:116][CH:111]([NH:110][C:108](=[O:109])[NH:8][CH:9]2[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]3[N:26]=[C:25]4[C:21]([N:22]=[CH:23][N:24]4[C@@H:27]4[CH2:31][C@H:30]([N:32]5[CH:36]=[C:35]([CH2:37][OH:38])[CH:34]=[N:33]5)[C@@H:29]([OH:39])[C@H:28]4[OH:40])=[C:20]([NH:41][CH2:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[N:19]=3)=[O:17])[CH2:11][CH2:10]2)[CH2:112][CH2:113]1
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: NC1CCC(NC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCC(NC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)CC1)NC1CCN(c2ccccn2)CC1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (4-amino-cyclohexyl)-amide trifluoroacetate (first step a) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethyl-amino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42). MS (ES+) m/e 428 (MH+/2)
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:14].[NH2:15][C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:19].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:20]2[C:18](=[O:19])[C:17]3[C:16](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=[C:9]2[C:8]2[CH:11]=[C:12]([CH3:13])[C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:6]([CH3:14])[CH:7]=2)=[CH:22][CH:23]=1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)cc(C)c1OCCO
Temperature: 155 °C

Procedure:
To a mixture of 4-(2-hydroxyethoxy)-3,5-dimethyl-benzaldehyde (0.420 g, 2.17 mmol) and 2-amino-N-(4-chloro-phenyl)-benzamide (0.500 g, 2.17 mmol) in N,N-dimethylacetamide (5 mL) was added sodium hydrogensulfite (0.350 g, 3.26 mmol) and p-toluenesulfonic acid (0.21 g, 0.11 mmol). The reaction mixture was heated at 155° C. for 14 hours, cooled to room temperature, and diluted with cold water (20 mL), to produce the precipitate. The yellow solid was filtered, washed with cold water, then methanol, and dried under vacuum to provide crude product, which was purified by preparative HPLC (0.1% TFA in CH3CN/H2O as eluent) to give the title compound as a white solid. Yield: 0.23 g (14%). MP 101-103° C. 1H-NMR (400 MHz, CDCl3): δ 8.38 (d, 1H), 7.81-7.78 (m, 2H), 7.59-7.51 (m, 1H), 7.31-7.20 (m, 2H), 7.15-7.12 (m, 2H), 7.01-6.98 (d, 2H), 3.98-3.80 (m, 4H), 2.20 (s, 6H), 2.01 (t, 1H). MS (ES+) m/z: 421.05 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13]>[OH-].[NH4+].O>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][C:12]([OH:14])=[O:13])=[C:2]([Br:1])[CH:7]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(CC(=O)O)c(Br)c1
Temperature: 25 °C

Procedure:
A solution of (2-bromo-4-nitrophenyl)acetic acid (500 mg, 2 mmol) in 11 mL of concentrated ammonium hydroxide was added a solution of FeSO4.7H2O (3.4 g, 12 mmol) in 11 mL of water over 5 minutes, and then the mixture was heated to reflux for 1 hour. Cooled to ambient temperature, filtered off solids and the filtrate was adjusted to pH to 5 with 2N HCl. Extracted with EtOAc and combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated to get (4-amino-2-bromophenyl)acetic acid. 1H-NMR (300 MHz, CDCl3) δ ppm 7.01 (d, J=8.0 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.62 (dd, J=2.5 Hz, 1H), 3.61 (s, 2H).
Reaction SMILES: N(CC(O)=O)C.[S:7]1(=[O:13])(=[O:12])[CH2:11][CH2:10][CH2:9][NH:8]1.[F:14][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][N:20]2[C:29](=[O:30])[C:28]([C:31]3[NH:36][C:35]4[CH:37]=[CH:38][C:39](I)=[CH:40][C:34]=4[S:33](=[O:43])(=[O:42])[N:32]=3)=[C:27]([OH:44])[C@H:26]3[C@@H:21]2[C@H:22]2[CH2:45][C@@H:25]3[CH2:24][CH2:23]2)=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I>[O:12]=[S:7]1(=[O:13])[CH2:11][CH2:10][CH2:9][N:8]1[C:39]1[CH:38]=[CH:37][C:35]2[NH:36][C:31]([C:28]3[C:29](=[O:30])[N:20]([CH2:19][C:18]4[CH:17]=[CH:16][C:15]([F:14])=[CH:47][CH:46]=4)[C@@H:21]4[C@H:26]([C:27]=3[OH:44])[C@@H:25]3[CH2:45][C@H:22]4[CH2:23][CH2:24]3)=[N:32][S:33](=[O:43])(=[O:42])[C:34]=2[CH:40]=1
Reactant: O=S1(=O)CCCN1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])[O-]
Product: O=C1C(C2=NS(=O)(=O)c3cc(N4CCCS4(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
A reaction flask was charged with copper (I) iodide (8 mg, 0.042 mmol), sarcosine (N-methyl glycine) (9 mg, 0.1 mmol), isothiazolidine 1,1-dioxide (204 mg, 1.685 mmol), (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 19, 100 mg, 0.168 mmol) and potassium phosphate (179 mg, 0.842 mmol). The flask was degassed and backfilled with nitrogen, and then anhydrous N,N-dimethylformamide (3 mL) was added. The resulting suspension was vigorously stirred at 100° C. for 17 h, and then allowed to cool to 25° C. The mixture was diluted with ethyl acetate (30 mL) and washed with 1.0M aqueous hydrochloric acid solution (2×20 mL) and saturated aqueous brine solution (40 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography (Teledyne Isco RediSep column; 1st column: 100% dichloromethane, 2nd column: 5% hexanes in dichloromethane) to afford the desired product. The crude product was triturated with absolute ethanol (3×) and dried in vacuo at 60° C. to afford the desired product, (1R,2S,7R,8S)-5-[7-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (70 mg, 0.119 mmol, 71%), as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.17-1.24 (2H, m), 1.40-1.61 (4H, m), 2.39-2.46 (2H, m), 2.51-2.54 (1H, m), 2.64-2.65 (1H, m), 3.03-3.05 (1H, m), 3.53-3.60 (3H, m), 3.83 (2H, t, J=6.3 Hz), 4.43 (1H, d, J=15.4 Hz), 4.97 (1H, d, J=15.6 Hz), 7.15 (2H, t, J=9.0 Hz), 7.32-7.35 (2H, m), 7.51-7.54 (2H, m), 7.62 (1H, d, J=8.5 Hz). LC-MS (ESI) calcd for C27H27FN4O6S2 586.14, found 587.4 [M+H+].
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl>CN(C)C1C=CC=CC=1>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(N)c1
Agent: Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Nine milliliters of acetyl chloride were added to a mixture of 18.4 g of ethyl 3-amino-4-nitrobenzoate and 200 ml of N,N-dimethylaniline while being cooled with ice. The mixture was stirred at room temperature for 2 hours and then at 50° C. for 2 hours. The reaction solution was poured into cold 1-N hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with 1-N hydrochloric acid and then with water, and was dried. The solvent was then distilled off under reduced pressure. The residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and hexane at a ratio of from 1:10 to 1:4) to give 19.6 g of ethyl 3-acetylamino-4-nitrobenzoate.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:24].[ClH:25].O1CCOCC1>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:24].[ClH:25]
Reactant: Cn1c(=O)ccc2cc(C3CCN(C(=O)OC(C)(C)C)C3)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1c(=O)ccc2cc(C3CCNC3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of tert-butyl 3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)pyrrolidine-1-carboxylate (1 mg) in CH2Cl2 (2 mL) was treated with 4 M HCl in dioxane (1 mL, 4 mmol). The mixture was stirred at rt for 3 h and concentrated to leave 1-methyl-6-(pyrrolidin-3-yl)quinolin-2(1H)-one as its HCl salt (1 mg). LC-MS Method 1 tR=1.48 min, m/z=229.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:12][CH2:11][N:5]2[C:6](=[O:10])[C:7]=1[N:8]=O.S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].O.[OH-].[Na+].[CH4:35]>C(O)=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:13]2[C:4]3=[N:3][C:2]4[NH:1][CH:35]=[N:8][C:7]=4[C:6](=[O:10])[N:5]3[CH2:11][CH2:12]2)=[CH:16][CH:17]=1
Reactant: Nc1nc2n(c(=O)c1N=O)CCN2Cc1ccc(Cl)cc1
Reactant: C
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: O=c1c2nc[nH]c2nc2n1CCN2Cc1ccc(Cl)cc1

Procedure:
The nitroso compound of Procedure 92 was reduced with sodium dithionate in formic acid according to the method of Procedure 21. The resulting 6-formylamino compound, 1.3 g. (0.0041 mole), was suspended in 40 ml. of water containing 0.0043 mole of NaOH and the mixture was heated on the steam bath until dissolution occurred. The solution was treated with charcoal, filtered, cooled and acidified with HOAc to yield the desired product, 0.85 g., recrystallized from MeOH, yield 0.60 g., hemihydrate m.p. 314°-316° d.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]([CH3:34])=[C:25]([CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:26]=2)=[CH:18][CH:17]=1>>[CH3:34][C:24]1[O:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=3)=[CH:17][CH:18]=2)=[N:26][C:25]=1[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: Cc1oc(-c2ccc(-c3cccc(OC(F)(F)F)c3)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 35 starting from 3-Trifluoromethoxybenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 417.1 (M+1)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][C:8]=2[S:9][C:10]=1[NH2:11])=O)C.[CH:21]([NH2:23])=O>>[O:3]=[C:4]1[NH:23][CH:21]=[N:11][C:10]2[S:9][C:8]3[CH2:12][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15][C:7]=3[C:6]1=2
Reactant: CCOC(=O)c1c(N)sc2c1CCC(C(=O)OCC)C2
Reactant: NC=O
Product: CCOC(=O)C1CCc2c(sc3nc[nH]c(=O)c23)C1
Temperature: 140 °C

Procedure:
In a 100 mL round-bottom flask was placed 3.5 g (11.75 mmol, 1 equiv) of 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3,6-dicarboxylic acid diethyl ester in 10 mL of formamide. The flask was equipped with a reflux condenser and heated at 140° C. for 16 h. The mixture was then allowed to cool to rt and a brown solid precipitated from solution. The resulting precipitate was filtered and rinsed with EtOAc (200 mL) and dried in a hi-vac oven for 2 h. After drying 3.25 g (99%) of the desired product as a brown solid was obtained and used without further purification in the next step. LCMS RT=2.80 min; [M+H]+=279.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH3:14])[N:6]=2.CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(Cl)Cl>[CH2:33]([O:32][C:30]([NH:1][C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH3:14])[N:6]=2)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1nc2nc(OCC)ccc2cc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc2nc(OCC)ccc2cc1NC(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 3-amino-7-ethoxy-1,8-naphthyridine-2-carboxylate (51 mg, 0.20 mmol) and DIPEA (100 μL, 0.58 mmol) in DCM (0.7 mL), benzyl chloroformate (84 μL, 0.58 mmol) was added and the reaction mixture was heated at 65° C. with stirring in a sealed vial for 16 h. The crude reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (24 g silica gel column, eluting with 0-40% EtOAc/hexanes) to afford the sub-title compound. LCMS (ESI) calc. for C21H22N3O5 [M+H]+: m/z=396.2. found: 396.1.
Reaction SMILES: [NH2:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=2)=[N:5][N:4]=[C:3]1[SH:19].[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=O)=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31]>P(Cl)(Cl)(Cl)=O>[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]2[S:19][C:3]3=[N:4][N:5]=[C:6]([C:7]4[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=4)[N:2]3[N:1]=2)=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31]
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: COc1cc(-c2nnc(S)n2N)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nnc3sc(-c4ccc(C)c([N+](=O)[O-])c4)nn23)cc(OC)c1OC
Yield: 87.9 %

Procedure:
A mixture of 4-amino-3-mercapto-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (220 mg, 0.78 mmol) and 4-methyl-3-nitrobenzoyl chloride (156 mg, 0.78 mmol) in phosphoryl chloride (2 mL) was refluxed for 3 h. The solvent was evaporated and the residue was dissolved in dichloromethane (20 mL). It was neutralized by aqueous sodium carbonate. The organic layer was dried over sodium sulfate, and concentrated to give 293 mg (85%) of the title compound as solid. 1H NMR (CDCl3): 8.59 (d, J=2.1 Hz, 1H), 8.05-8.01 (dd, J=7.8, 1.8 Hz, 1H), 7.73 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 4.02 (s, 6H), 3.95 (s, 3H), 2.75 (s, 3H).