Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: 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.[F:34][C:35]1[CH:40]=[C:39]([C:41]2[O:42][CH:43]=[C:44]([CH2:46][N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[N:45]=2)[CH:38]=[CH:37][C:36]=1[OH:53].[N:54]1([CH2:60][CH2:61][CH2:62]O)[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1.Cl>O1CCCC1>[F:34][C:35]1[CH:40]=[C:39]([C:41]2[O:42][CH:43]=[C:44]([CH2:46][N:47]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]3)[N:45]=2)[CH:38]=[CH:37][C:36]=1[O:53][CH2:62][CH2:61][CH2:60][N:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: OCCCN1CCCCC1
Reactant: Oc1ccc(-c2nc(CN3CCCCC3)co2)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cc(-c2nc(CN3CCCCC3)co2)ccc1OCCCN1CCCCC1
Reaction time: 48 h
Yield: 20 %

Procedure:
To a solution of triphenylphosphine (0.81 g, 3.08 mmol, 1 eq) in dry tetrahydrofuran at 0° C. is added dropwise diisopropylazodicarboxylate (0.61 ml, 3.08 mmol, 1 eq). A solution of 2-fluoro-4-[4-(1-piperidinylmethyl)-1,3-oxazol-2-yl]phenol i68 (0.85 g, 3.08 mmol, 1 eq) and 3-(1-piperidinyl)-1-propanol (0.44 g, 3.08 mmol, 1 eq) in tetrahydrofuran is added dropwise to the mixture at 0° C. After 2 days, the mixture is poured onto 0.5 N hydrochloric acid and extracted with diethyl ether. The aqueous phase is basified with 1 N sodium hydroxide to pH 9 and extracted with ethyl acetate. The organic layer is dried on magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography over silica gel to afford 0.25 g of 1-(3-{2-fluoro-4-[4-(piperidin-1-ylmethyl)-1,3-oxazol-2-yl]phenoxy}propyl)piperidine 88 as a yellow oil.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=O)[CH:29]([NH:35][C:36]([C:38]1[O:42][N:41]=[C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:39]=1[C:49]([F:52])([F:51])[F:50])=O)[CH2:28][CH2:27]2>C1(C)C=CC=CC=1>[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30]1[S:10][C:36]([C:38]3[O:42][N:41]=[C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:39]=3[C:49]([F:52])([F:51])[F:50])=[N:35][C:29]=1[CH2:28][CH2:27]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(NC1CCc2cc(Br)ccc2C1=O)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: Cc1ccccc1
Product: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc2c(s1)-c1ccc(Br)cc1CC2
Temperature: 140 °C
Yield: 85.4 %

Procedure:
To Lawesson's Reagent (1.393 g, 3.44 mmol) was added N-(6-bromo-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxamide (Preparation 82C, 1.1 g, 2.295 mmol) followed by toluene (10 mL). The reaction mixture was heated at 140° C. behind a safety shield for 15 h. The reaction mixture was cooled to room temperature, loaded onto a silica gel column (with toluene) and purified using hexane/EtOAc (9.25:0.75, 600 mL). The desired fractions were collected and concentrated to yield a pale yellow solid. The solid was triturated with acetonitrile (20 mL), filtered and washed with acetonitrile (2×5 mL) to yield 5-(7-bromo-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)-3-phenyl-4-(trifluoromethyl)isoxazole (0.935 g, 1.959 mmol, 85% yield) as a pale yellow solid. LC/MS M+1=478.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]#[N:17])=[C:5]2[C@@H:4]2[CH2:18][CH2:19][N:3]12.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:27][OH:28]>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16](=[N:27][OH:28])[NH2:17])=[C:5]2[C@@H:4]2[CH2:18][CH2:19][N:3]12
Reactant: NO
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Yield: 93.7 %

Procedure:
64.7 g (258 mmol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile were heated to reflux for 2.5 hours with 52.8 g (497 mmol) of sodium carbonate and 42.36 g (608 mmol) of hydroxylamine hydrochloride in 1.5 l of alcohol and 300 ml of water. The alcohol was evaporated and the suspension obtained was cooled to 0°. The crystals were filtered off under suction, washed with water and dried. There were obtained 68.5 g (93%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime of decomposition point 216°.
Reaction SMILES: [CH2:1]([C:9]#[N:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:11][CH2:12][CH2:13]N>C([O-])(=O)C.[Zn+2].C([O-])(=O)C.C(O)CCC>[CH2:1]([C:9]1[O:11][CH2:12][CH2:13][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCCO
Reactant: CCCCCCCCC#N
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CCCCO
Product: CCCCCCCCC1=NCCO1
Temperature: 120 °C
Yield: 46.6 %

Procedure:
A mixture of octyl cyanide (75.0 g, 0.539 mol), anhydrous zinc acetate (2.47 g, 0.0134 mol) and 1-butanol (270 ml) was stirred at 120° C. under nitrogen. To this mixture was dropwisely added 2-hydroxyethyl amine (39.5 g, 0.647 mol) in 20 min., and the resulting mixture was stirred at 120° C. for 40 h. The resulting admixture was distilled under reduced pressure three times. The fraction at 75°-80° C./0.2 mmHg was collected to give 2-octyl-2-oxazoline as a colorless liquid (46 g, 47% yield). The product was again distilled under reduced pressure from calcium hydride: 1H NMR (CDCl3) delta 0.88 (5, J=6.6 Hz, 3H, CH3), 1.29 (m, 10H, CH2×8), 1.63 (t of t, J=6.6 and 6.9 Hz, 2H, CH2), 2.26 (t, J=7.2 Hz, 2H, CH2), 3.82 (t, J=9.6 Hz, 2H, CH2O), and 4.22 (t, J=9.6, 2H, CH2N).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[N:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[N:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: O=Cc1cn[nH]c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C=O)cn3)ccc2n1CC1CCOCC1
Yield: 29.6 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (3.26 g, 8.8 mmol), 1H-pyrazole-4-carbaldehyde (1.01 g, 10.5 mmol) and DMAP (2.15 g, 17.6 mmol) in MeCN (70 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 1.12 g (30%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.39-1.56 (m, 4 H), 1.58 (s, 9 H), 2.21-2.36 (m, 1 H), 3.29-3.33 (m, 2 H), 3.88 (m, 2 H), 4.40 (d, J=7.42 Hz, 2 H), 5.41 (s, 1 H), 7.69 (s, 1 H), 7.84-7.90 (m, 1 H), 7.92-7.97 (m, 1 H), 8.25 (t, J=0.68 Hz, 1 H), 8.29 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=430.7; Anal. Calcd for C21H26N4O4S+0.80 TFA+0.30 CH3CN+0.20H2O (537.67): C, 51.83; H, 5.27; N, 11.20. Found: C, 51.79; H, 5.20; N, 11.16.
Reaction SMILES: C(Cl)CCl.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:6]=1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH2:26][NH:27][CH3:28].C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[CH3:28][N:27]([CH2:26][C:18]1[N:17]([CH3:16])[C:25]2[C:20]([CH:19]=1)=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13](=[O:15])/[CH:12]=[CH:11]/[C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: O=C(O)/C=C/c1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cccnc1
Reaction time: 8 h
Yield: 40.2 %

Procedure:
EDC (0.22 g, 1.14 mmole) was added to a solution of trans-3-(3-pyridyl)acrylic acid (0.17 g, 1.14 mmole), 1-methyl-2-(methylaminomethyl)-1H-indole (0.20 g, 1.15 mmole), and HOBt.H2O (0.15 g, 1.11 mmole) in DMF (10 mL) at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over MgSO4. Flash chromatography on silica gel (3% MeOH/CH2Cl2) followed by preparative TLC (3% MeOH/CH2Cl2) gave the title compound (0.14 g, 40%) as a white solid: 1H NMR (360 MHz, CDCl3) indicated an approximately 8:1 mixture of amide rotamers; for the major rotamer: δ 8.79 (s, 1H), 8.59 (d, J=3.9 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.76 (d, J=15.5 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.38-7.48 (m, 2H), 7.19-7.27 (m, 1H), 7.08-7.17 (m, 1H), 6.98 (d, J=15.5 Hz, 1H), 6.51 (s, 1H), 4.94 (s, 2H), 3.73 (s, 3H), 3.09 (s, 3H); MS (ES) m/e 306 (M+H)+. Anal. Calcd for C19H19N3O.0.20H2O: C, 73.86; H, 6.33; N, 13.60. Found: C, 73.52; H, 6.32; N, 13.43.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:14](#[N:18])[CH2:15][C:16]#[N:17].N1CCCCC1>C(O)C>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([Br:1])[C:3]=1[O:12][CH3:13])[CH:7]=[C:15]([C:14]#[N:18])[C:16]#[N:17]
Reactant: N#CCC#N
Reactant: COc1cc(C=O)cc(Br)c1OC
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C=C(C#N)C#N)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 5-bromoveratraldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) in ethanol was added piperidine (0.1 ml, 1 mmol). The mixture was stirred at room temperature for 15 min to give the product 3,4-dimethoxy-5-bromobenzylidenemalononitrile as a yellow precipitate.
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[C:7]([OH:21])=[C:8]([S:13]([NH:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:15])=[O:14])[C:9]([Cl:12])=[CH:10][CH:11]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:30]([NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Cl:22])=[O:31])=[C:7]([OH:21])[C:8]=1[S:13]([NH:16][CH2:17][CH:18]1[CH2:20][CH2:19]1)(=[O:14])=[O:15]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1O
Yield: 21.1 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 3-amino-6-chloro-N-cyclopropylmethyl-2-hydroxybenzenesulfonamide (0.23 g, 0.77 mmol) and 2-chlorophenylisocyanate(95 μL, 0.79 mmol) were coupled to form the desired urea (0.07 g, 21%). LC-MS m/z 430 (M+).
Reaction SMILES: C1(C2C3C=CC(C([O-])=O)=CC=3N3C=2C2C=CC=CC=2OCC2(COC(C)(C)OC2)C3)CCCCC1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[CH:44]1([C:50]2[C:51]3[CH:52]=[CH:53][C:54]([C:72]([O:74][CH3:75])=[O:73])=[CH:55][C:56]=3[N:57]3[C:67]=2[C:66]2[CH:68]=[CH:69][CH:70]=[CH:71][C:65]=2[O:64][CH2:63][C:59]2([CH2:62]O[CH2:60]2)[CH2:58]3)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>CCOC(C)=O>[CH2:36]([N:43]1[CH2:62][C:59]2([CH2:58][N:57]3[C:56]4[CH:55]=[C:54]([C:72]([O:74][CH3:75])=[O:73])[CH:53]=[CH:52][C:51]=4[C:50]([CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)=[C:67]3[C:66]3[CH:68]=[CH:69][CH:70]=[CH:71][C:65]=3[O:64][CH2:63]2)[CH2:60]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(COC1)COc1ccccc1-3
Agent: CC1(C)OCC2(COc3ccccc3-c3c(C4CCCCC4)c4ccc(C(=O)[O-])cc4n3C2)CO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(COc2ccccc2-3)CN(Cc2ccccc2)C1
Yield: 65 %

Procedure:
This compound was prepared from 14′-cyclohexyl-2,2-dimethylspiro[1,3-dioxane-5,7′-indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylate (Example 2, Step 3) and benzylamine as described in Example 9. Flash chromatography (PE:EtOAc 2:1) gave a mixture of the title compound and methyl 14-cyclohexylspiro[indolo[1,2-e][1,5]benzoxazocine-7,3′-oxetane]-11-carboxylate in 65% yield. MS (ES+) m/z 521 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([O:14][CH2:15][CH:16]=O)[CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:24][OH:25]>C(O)C.O>[CH2:1]([O:8][CH2:9][C@H:10]([O:14][CH2:15][CH:16]=[N:24][OH:25])[CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: C=CC[C@H](COCc1ccccc1)OCC=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CC[C@H](COCc1ccccc1)OCC=NO
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
{[(2R)-1-(Benzyloxy)pent-4-en-2-yl]oxy}acetaldehyde (C3) (7.76 g, ≦32.88 mmol) was dissolved in a 2:1 mixture of ethanol and water (127 mL). Sodium acetate (13.6 g, 166 mmol) was added, and the mixture was stirred for 15 minutes. Hydroxylamine hydrochloride (98%, 7.05 g, 99.4 mmol) was then added, and the reaction mixture was heated to 60° C. for 18 hours. The reaction mixture was partitioned between ethyl acetate and water; the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 30% ethyl acetate in heptane) afforded the product as a colorless oil, presumed from the 1H NMR spectrum to be a mixture of E and Z oximes. Yield: 7.12 g, 28.6 mmol, 87% over two steps. 1H NMR (400 MHz, CDCl3) δ 2.30-2.37 (m, 2H), 3.47-3.65 (m, 3H), {[4.20 (dd, half of ABX pattern, J=12.9, 5.8 Hz) and 4.25 (dd, half of ABX pattern, J=12.9, 5.6 Hz)] and 4.45-4.49 (br m), total 2H}, 4.55 and 4.56 (2 s, total 2H), 5.05-5.14 (m, 2H), 5.75-5.87 (m, 1H), 6.93-7.01 and 7.47-7.55 (2 br m, total 1H), 7.27-7.39 (m, 5H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9]O[C:6]=2[CH2:5][CH2:4][N:3]1[CH2:16][CH3:17].C([O-])(=O)C.[NH4+:22]>CN(C)C=O>[O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:22][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:16][CH3:17]
Reactant: [NH4+]
Reactant: CCOC(=O)c1coc2c1C(=O)N(CC)CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2c1C(=O)N(CC)CC2
Temperature: 115 °C
Yield: 53.6 %

Procedure:
A mixture of ethyl 4-oxo-5-ethyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine-3-carboxylate (3.66 g, 15.4 mmol) and ammonium acetate (5.94 g, 77.1 mmol) in N,N-dimethylformamide (30 mL) was heated at 115° C. for 23 hours. The mixture was cooled, concentrated in vacuo, ice water added, and the precipitate collected and dried to give ethyl 4-oxo-5-ethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-3-carboxylate (1.95 g). The aqueous filtrate was extracted 2× with ethyl acetate, the combined organic layers dried over magnesium sulfate, filtered, and concentrated in vacuo to afford additional ester (0.68 g). The combined materials were treated with aqueous 5N sodium hydroxide (75 mL) in dioxane (10 mL) at reflux for 2 hours. After cooling in an ice water bath, the mixture was acidified with aqueous hydrochloric acid, and concentrated in vacuo. Ethyl acetate was added, the mixture filtered, and the organic layer concentrated in vacuo. Trituration with ethyl acetate afforded 4-oxo-5-ethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid (0.84 g).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N:10]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[F:26])[C:13]3[CH:27]=[CH:28][CH:29]=[CH:30][C:12]=3[S:11]2(=[O:32])=[O:31])=[CH:5][C:4]=1[CH3:33].B(Br)(Br)Br.CCCCCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[OH:2][C:3]1[C:4]([CH3:33])=[CH:5][C:6]([N:10]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[C:19]([F:26])=[CH:20][C:21]([F:25])=[CH:22][C:23]=3[F:24])[C:13]3[CH:27]=[CH:28][CH:29]=[CH:30][C:12]=3[S:11]2(=[O:32])=[O:31])=[CH:7][C:8]=1[CH3:9]
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc(C)c1O
Yield: 57.1 %

Procedure:
To a solution of (115) (0.2 g, 0.42 mmol) in DCM (5 mL) was added boron tribromide (1.0M solution in DCM, 0.46 mL, 0.46 mmol) at −70° C. The resulting mixture was stirred for approximately two h at rt with TLC monitoring (hexane:EtOAc, 1:1). The reaction mixture was poured into saturated aqueous NaHCO3 solution (50 mL), extracted with EtOAc (3×50 mL), and the combined organic layer was dried over Na2SO4 and concentrated in vacuo. Purification by trituration with DCM in pentane (1:9) yielded the title compound (0.11 g, 0.24 mmol).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:13]([OH:15])=[O:14]>C(OC(=O)C)(=O)C>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:4]2[C:5]([O:15][C:13](=[O:14])[C:3]=12)=[O:7]
Reactant: COc1ccc(C(=O)O)c(C(=O)O)c1F
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1F)C(=O)OC2=O
Temperature: -60 °C
Yield: 81.7 %

Procedure:
To a solution of 2-(3-fluoro-4-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (34.0 g) in dry tetrahydrofuran (300 ml) sec-butyllithium (140 ml of a 1.3 M solution in cyclohexane) was added dropwise at -78° C. with stirring, under nitrogen. The reaction mixture was stirred 15 mins, and carbon dioxide was bubbled below the surface. The reaction was stirred for 1 hr and water added dropwise. The mixture was basified with 10% sodium hydroxide solution and extracted with ethyl acetate. The aqueous extract was cooled to 0° C. and an equal volume of concentrated hydrochloric acid was added dropwise. The solution was stirred, under reflux overnight, cooled and the solid collected. The solid was washed with cold water and dried in vacuo to give 26.6 g of 3-fluoro-4-methoxyphthalic acid. A mixture of 3-fluoro-4-methoxyphthalic acid (26.6 g ) in acetic anhydride (100 ml) was stirred, under reflux, under nitrogen, for 4 hrs. The reaction mixture was cooled to -60° C. and filtered. The solid was collected, washed with ether and dried in vacuo to give 19.9 g (67%) of 3-fluoro-4-methoxyphthalic anhydride, mp 128-130° C. A mixture of 3-fluoro-4-methoxyphthalic anhydride (10.0 g) and 4-hydrazinopyridine hydrochloride (7.42 g) in glacial acetic acid (50 ml) was stirred, under reflux, under nitrogen, for 4 hrs and stirred at ambient temperature overnight. The solid was collected, washed with ether and dried in vacuo at 80° C. overnight to give 10.6 g (64%) of 4-fluoro-5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione. To a mixture of lithium aluminum hydride (3.72 g) and dry tetrahydrofuran (100 ml), 4-fluoro-5-methoxy-2-(4-pyridinylamino)isoindole-1,3-dione hydrochloride (10.60 g) was added in portions with rapid stirring, under nitrogen, at ambient temperature. The reaction mixture was stirred at ambient temperature, under nitrogen, for 3 hrs, and sodium sulfate decahydrate was added in portions. The mixture was filtered through a bed of celite, the filter pad was washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel, eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane:methanol:ammonium hydroxide. The residue was crystallized from absolute ethanol to give 3.2 g (8%) of product, (dried under vacuum at 80° C. overnight) mp 206-210° C.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13])=[CH:3][Cl:4].[CH3:16][N:17]=[C:18]=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:18]([NH:17][CH3:16])=[O:19])(=[O:13])=[O:14])=[CH:3][Cl:4]
Reactant: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)NS(=O)(=O)c1ccccc1OC(Cl)=CCl

Procedure:
A suspension of 6.7 g of 2-(1,2-dichlorovinyloxy)phenylsulfonamide in 50 ml of methylene chloride is treated with 1.9 g of methyl isocyanate. 3.3 g of triethylamine are added dropwise to this mixture at a temperature of 20°-25° C. within 10 minutes resulting in a clear solution. The solution is stirred for a further hour and evaporated to dryness. The residue is solved in 5% aqueous sodium carbonate and acidified with a 10% solution of hydrochloric acid yielding 7.8 g of N-[2-(1,2-dichlorovinyloxy)-phenylsulfonyl]-N'-methyl urea, m.p. 225°-226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Br:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Br:23])[CH:25]=3)[CH2:35][CH2:34]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=S)N1CCN(c2cccc(Br)c2)CC1
Yield: 57.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(3-bromophenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: Br[CH:2]([CH:7]([OH:10])[CH2:8][Br:9])[C:3]([O:5][CH3:6])=[O:4].C([O-])(=O)C.[Na+]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[Br:9][CH2:8][C@@H:7]([OH:10])[CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Br)C(O)CBr
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C[C@H](O)CBr
Reaction time: 2 h

Procedure:
An argon purged solution of the dibromide obtained in step (b) above (20.8 g, 75.4 mM) and anhydrous sodium acetate (NaOAc) (21.0 g) in ethyl acetate (370 ml) and glacial acetic acid (37 ml) was treated with 5% Pd/C (1.30 g) and the black suspension stirred under one atmosphere of H2 while monitoring uptake (22.4 l/mole). After 2.0 hours H2 uptake was complete, the mixture was filtered through Celite, the filtrate washed with saturated NaHCO3 and brine and then dried over anhydrous MgSO4 and evaporated to give the crude bromoester title product as a brown oil. The crude oil was combined with another batch (starting from 36.77 g of the dibromide) and vacuum distilled to give 25.771 g (61.3%) of the pure bromoester title product as a clear oil with b.p.=79°-80° C. (1.0 mm Hg) and with consistent C13NMR spectral data. TLC (1:1) ethyl acetatehexane, Rf=0.44, PMA.
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=1[F:17]>CO.[Pd]>[CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[F:17]
Reactant: C[Si](C)(C)CCOC(=O)Nc1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)CCOC(=O)Nc1cc(N)ccc1F
Reaction time: 24 h
Yield: 96.9 %

Procedure:
A mixture of (2-Fluoro-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (3.00 g, 10 mmol) and 10% Pd/C (300 mg) in methanol (30 ml) was hydrogenated at 23° C. The resulting mixture was stirred for 24 h. The reaction mixture was filtered through celite and concentrated to give (5-Amino-2-fluoro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (2.62 g, 97%). 1H NMR (300 MHz, CDCl3) δ 7.52 (m, 1H), 6.85 (dd, 1H, J=10.8 Hz, J=8.69 Hz), 6.73 (bs, 1H), 6.28 (m, 1H), 4.27 (t, 2H, J=8.57 Hz), 3.0–4.4 (bs, 2H), 1.06 (t, 2H, J=8.58 Hz), 0.07 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-]>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc2cnc(Nc3ccnc(C)c3)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc3cc(C(=O)O)ccc3cn2)ccn1
Reaction time: 3 h

Procedure:
A slurry of 96 (132 mg, 0.45 mmol) in THF (2.19 mL) and water (0.324 mL) was treated with solid LiOH (24 mg, 0.99 mmol) and stirred for 3 h. THF was removed in vacuo, and the mixture was suspended in water (6.0 mL) and treated with aqueous HCl (10 M, 0.27 mL). A yellow-brown precipitate was collected by vacuum filtration to afford 3-(2-methylpyridin-4-ylamino)isoquinoline-6-carboxylic acid (98) as a yellow solid, which was used in subsequent steps without further purification.