Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]1[CH2:15][CH2:14][C@@:13]23[C:16]4[C:22]5[CH2:23][C@@H:3]1[C@@H:4]2[CH2:5][CH2:6][C:7]1([C@@H:12]3[O:18][C:17]=4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=5)[O:11][CH2:10][CH2:9][O:8]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CC1(C)CC(=O)CC(=O)C1.CO.Cl>CN(C)C=O>[O:8]1[CH2:9][CH2:10][O:11][C:7]21[CH2:6][CH2:5][C@@H:4]1[C@@:13]34[C:16]5[C:22](=[CH:21][CH:20]=[C:19]([C:24]#[N:25])[C:17]=5[O:18][C@@H:12]23)[CH2:23][C@H:3]1[NH:2][CH2:15][CH2:14]4
Reactant: CN1CC[C@]23c4c5ccc(C#N)c4O[C@H]2C2(CC[C@H]3[C@H]1C5)OCCO2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1ccc2c3c1O[C@H]1C4(CC[C@H]5[C@@H](C2)NCC[C@@]351)OCCO4
Temperature: 55 °C
Yield: 81 %

Procedure:
To a suspension of (4R,4aR,7aR,12bS)-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile (5.0 g, 17.8 mmol) in dimethylformamide (50 mL) was added diisopropyl azodicarboxylate (5.4 mL, 27.5 mmol). The reaction was heated to 55° C. for 3 hours until the starting material was consumed. To the reaction was added dimedone (5.8 g, 41.4 mmol) and methanol (1.75 mL, 54.8 mmol) and the reaction heated to 60° C. for 3 hours. The reaction was allowed to cool to room temperature and poured into 0.5 M HCl(aq) (50 mL). The aqueous phase was washed with diethyl ether: ethyl acetate (3:1). The organic phase was back extracted with 0.5 M HCl(aq) and acidic phases combined before basifying with 2M NaOH until pH9. The aqueous phase was extracted with ethyl acetate (×3). The combined organic phases were washed with water/brine (×3) before drying over MgSO4 and concentrating under reduced pressure. The residue was purified by silica chromatography (5% methanol in dichloromethane to 5% NH3/methanol in dichloromethane) to give to (4R,4aR,7aR,12bS)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile as a pale yellow solid (3.90 g, 95% pure LCMS, 81% yield); [M+H]+ 325.1.
Reaction SMILES: [C:1](=[S:3])=S.C(N(CC)CC)C.[NH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[C:15]([CH2:22][O:23][CH2:24][CH3:25])[N:16]=[CH:17]2.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH2:24]([O:23][CH2:22][C:15]1[N:16]=[CH:17][C:18]2[C:13]([CH:14]=1)=[C:12]([N:11]=[C:1]=[S:3])[CH:21]=[CH:20][CH:19]=2)[CH3:25]
Reactant: CCOCc1cc2c(N)cccc2cn1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOCc1cc2c(N=C=S)cccc2cn1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A solution of carbon disulphide (16 cc) and triethylamine (4.5 cc) in pyridine (20 cc) is cooled to -10° C. A solution of 5-amino-3-ethoxymethylisoquinoline (6.5 g) in pyridine (20 cc) is added dropwise in the course of 5 minutes. The mixture is stirred for 3 hours at -10° C. and a solution of dicyclohexylcarbodiimide (6.6 g) in pyridine (20 cc) is then added. Stirring is continued, whilst leaving the reaction mixture to return to a temperature of about 20° C. The mixture is stirred for 24 hours at this temperature and then concentrated to dryness at 50° C. under reduced pressure (20 mm Hg). The residue is taken up in methylene chloride (25 cc). An insoluble material is filtered off and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg). The residue is taken up in diisopropyl ether (200 cc). The isoluble yellow solid is isolated by filtration, washed with diisopropyl ether (20 cc) and dried. 3-Ethoxymethyl-5-isothiocyanatoisoquinoline (7 g), melting at 66° C., is obtained.
Reaction SMILES: Br[CH:2]([C:4]1[C:5]([F:27])=[CH:6][C:7]2[O:16][CH2:15][CH2:14][N:13]3[C:9](=[N:10][C:11]([C:17]4[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=4)=[CH:12]3)[C:8]=2[CH:26]=1)[CH3:3].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:27][C:5]1[C:4]([CH:2]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[CH3:3])=[CH:26][C:8]2[C:9]3[N:13]([CH:12]=[C:11]([C:17]4[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=4)[N:10]=3)[CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C(C)Br)c(F)cc2OCC3)n(C(C)C)n1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn3c(n2)-c2cc(C(C)N4CCN(C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Yield: 63.3 %

Procedure:
A solution of 9-(1-bromoethyl)-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 374 (99 mg, 0.23 mmol), N-methylpiperazine (28 μL, 0.25 mmol) and DIPEA (60 μL, 0.35 mmol) in dioxane (1 mL) was stirred at RT for 72 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (Si-PPC, gradient 0-8% 2 M NH3/MeOH in DCM) to give 66 mg of a pale yellow oil. The compound was further purified by reverse phase column chromatography (C18, gradient 2-50% MeOH in 1% TFA/H2O) and then loaded in MeOH onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2 M NH3 in MeOH. The basic fraction was concentrated in vacuo to afford 373 (47 mg, 40% over 2 steps) as a white solid. LCMS (Method K): RT 2.70 min [M+H]+ 454.2. 1H NMR (CD3OD, 400 MHz): δ 8.54 (1H, d, J=8.6 Hz), 7.68 (1H, s), 6.76 (1H, d, J=11.0 Hz), 5.83 (1H, sept., J=6.7 Hz), 4.49 (4H, br s), 3.84 (1H, q, J=6.8 Hz), 2.47 (8H, br s), 2.33 (3H, s), 2.22 (3H, s), 1.53 (3H, d, J=6.7 Hz), 1.52 (3H, d, J=6.7 Hz), 1.40 (3H, d, J=6.8 Hz)
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([CH:51]=[CH:52][CH:53]=1)[NH:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:49][CH3:50])=[C:39]([O:42][CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[CH:40]=2)[N:35]=[CH:34][N:33]=1.[C:55](O)(=[O:58])[CH2:56][OH:57].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([CH:51]=[CH:52][CH:53]=1)[NH:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([O:49][CH3:50])=[C:39]([O:42][CH:43]3[CH2:48][CH2:47][N:46]([C:56](=[O:57])[CH2:55][OH:58])[CH2:45][CH2:44]3)[CH:40]=2)[N:35]=[CH:34][N:33]=1
Reactant: O=C(O)CO
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CO)CC1

Procedure:
HATU (28.9 g) was added to a stirred solution of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-4-yloxy)quinazoline dihydrochloride (30 g), glycolic acid (5.40 g) and di-isopropylethylamine (44.70 ml) in methylene chloride (900 ml). After 1.5 hours the reaction mixture was washed with sodium hydroxide solution (2M), water and saturated brine. The resulting product was then purified by flash chromatography on silica eluting with 3% MeOH/methylene chloride. The fractions containing the desired product were combined and reduced in vacuo to give the title product as a white solid which was recrystallised from acetonitrile (29.6 g); NMR Spectrum: (DMSO d6) 1.65–1.81 (m, 2H), 1.99–2.10 (m, 2H), 3.26–3.34 (m, 1H), 3.37–3.47 (m, 1H), 3.60–3.68 (m, 1H), 3.81–3.89 (m, 1H), 3.95 (s, 3H), 4.14 (d, 2H), 4.50 (t, 1H), 4.78 (m, 1H), 7.25 (s, 1H), 7.30 (t, 1H), 7.46–7.55 (m, 2H), 7.88 (s, 1H), 8.40 (s, 1H), 9.55 (s, 1H); Mass Spectrum: (M+H)+ 460.94.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:30][C:29]=1[O:38][CH3:39]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:37])[CH3:36])=[CH:30][C:29]=4[O:38][CH3:39])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(CC(C)=O)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(CC(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 31.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 15.2 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]propanone (4.6 g, 18.2 mmol) acetonitrile (100 ml) was heated at reflux for 2 hours. At the end of the reaction, the mixture was filtered and the solvent was concentrated and the residue was extracted into dichloromethane (300 ml). The dichloromethane was filtered and concentrated again. The crude material (6.4 g) was purified by flash chromatography over a silica gel column (SiO2, 50 g; eluted with dichloromethane, 700 ml; 1% methanol in dichloromethane, 1.4 1). The material thus purified (weight: 2.87 g, 51%) was recrystallized from ethanol (25 ml) to give 2.13 g of 1-[4-[3-[4-(6-fluoro-1,2--benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]propanone as beige colored crystals, m.p.=118°-119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][NH:14][C@@H:13]([CH3:17])[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[N:28][C:27]([C:30](O)=[O:31])=[N:26]2)[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH:29]=[N:28][C:27]([C:30]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)=[O:10])[CH2:12][C@@H:13]3[CH3:17])=[O:31])=[N:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Reactant: COc1cccc(C(=O)N2CCN[C@@H](C)C2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2CCN(C(=O)c3ncn(-c4cccc(Cl)c4)n3)[C@@H](C)C2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 71 mg (0.30 mmol) (6-methoxy-pyridin-2-yl)-((S)-3-methyl-piperazin-1-yl)-methanone, 67 mg (0.30 mmol) 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid, 0.11 g (0.33 mmol) TBTU and 77 μL (0.450 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23]1.C(OCC)C>C(Cl)(Cl)Cl>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:28])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: O=C1CCC(=O)O1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51929.6 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.14 g) obtained in Example 1d) in chloroform (10 ml) was added succinic anhydride (0.06 mg), and the mixture was stirred at room temperature for 3 days. Diethyl ether was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with diethyl ether to give the title compound as a pale-brown powder (0.12 g, 63%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[C:53]([C:56]1[N:57]=[N:58][NH:59][CH:60]=1)(O)=[O:54]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:53]([C:56]2[N:57]=[N:58][NH:59][CH:60]=2)=[O:54])[CH2:25]1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)c1c[nH]nn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CN(C(=O)c2c[nH]nn2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 72 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 4-carboxy-1,2,3-triazole as the starting materials in 72% yield. LCMS for C25H24ClN10O2 (M+H)+: m/z=531.0.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:12][NH2:13].CO>C1COCC1>[F:1][C:2]1[C:3]([C:9]([NH:13][CH3:12])=[O:11])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1ncc(F)cc1F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
N,N′-carbonyldiimidazole (600 mg) was added to a solution of 3,5-difluoropyridine-2-carboxylic acid (500 mg) in THF (10 ml), followed by stirring at 50° C. for one hour. The reaction solution was returned to room temperature, a 40% methylamine/methanol solution (1 ml) was added thereto, followed by stirring at room temperature for one hour. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 0:100 linear gradient) to obtain 3,5-difluoro-N-methylpyridine-2-carboxamide (293 mg) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH3:11].C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH2:11][Br:20]
Reactant: COC(=O)c1ccc(F)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(F)cc1CBr
Yield: 91.1 %

Procedure:
A mixture of 4-fluoro-2-methyl-benzoic acid methyl ester (12.7 g, 75.5 mmol), NBS (13.4 g, 75.5 mmol), and di-benzoyl peroxide (BPO) (0.85 g, 3.5 mmol) in CCl4 (200 mL) was heated to reflux for 3 hours until all starting material was consumed. After vacuum filtration, the filtrate concentrated in vacuo to give a crude product (17 g, yield 91%), which was used in the next step reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(C=O)cc1
Yield: 71.5 %

Procedure:
By the method of Example 1, Step H, 10.0 g (0.0819 mole) of 4-hydroxybenzaldehyde and 16.4 g (0.0983 mole) of methyl 2-bromopropionate were reacted in the presence of 13.6 g (0.0983 mole) of anhydrous potassium carbonate in N,N-dimethylformamide, yielding 12.2 g of methyl 2-(4-formylphenoxy)propionate as a yellow liquid. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]=1[CH2:18][OH:19]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCC1=C(Cl)c2ccccc2OC1c1ccccc1

Procedure:
To a stirred solution of 16 g 4-chloro-3-formyl-flav-3-ene in 500 ml dry methanol at room temperature is added 0.5 g sodium borohydride in small portions. After the addition is completed 500 ml water is added. The solution is filtered and extracted with chloroform. The combined organic extracts are dried over magnesium sulfate and evaporated. Chromatographically pure 4-chloro-3-hydroxymethyl-flav-3-ene is obtained as a yellowish oil; TLC (SiO2, CHCl3): 1 spot, RF 0.18.
Reaction SMILES: C(O)C=C.CC(C)([O-])C.[K+].[C:11]([S:14][CH2:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[CH:18][CH:17]=1)(=O)[CH3:12].C([O:31][CH:32]1[NH:35]C(=O)C1)(=O)C>O1CCCC1>[CH2:23]([O:22][C:20]([C:19]1[CH:26]=[CH:27][C:16]([CH2:15][S:14][CH:11]2[NH:35][C:32](=[O:31])[CH2:12]2)=[CH:17][CH:18]=1)=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)c1ccc(CSC(C)=O)cc1
Reactant: CC(=O)OC1CC(=O)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCO
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc(CSC2CC(=O)N2)cc1
Reaction time: 1 h
Yield: 82 %

Procedure:
Allyl alcohol (27 ml) in dry tetrahydrofuran (50 ml) was added dropwise to a solution of potassium tert-butoxide (4.93 g, 0.044 moles) in dry tetrahydrofuran (100 ml). After stirring for 5 minutes a solution of allyl 4-(acetylthiomethyl)benzoate (10.1 g, 0.04 moles) in dry tetrahydrofuran (100 ml) was added dropwise. After stirring for 15 minutes a solution of 4-acetoxyazetidin-2-one (5.16 g, 0.04 moles) was added dropwise. The mixture was stirred for 1 hour and evaporated. The residue was partitioned between ethyl acetate and water and the aqueous was extracted with ethyl acetate. The combined extracts were washed with brine, dried and evaporated. Flash chromatography (silica gel, ethyl acetate-petrol) gave 4-(4-Allyloxycarbonylbenzylthio)azetidin-2-one as an oil (9.1 g, 82% yield. 1H NMR δ (CDCl3) 2.84 (1H, dd, H3a), 4.31 (1H, dd, H3b), 3.88 (2H, s, S--CH2), 4.68 (1H, dd, H4), 4.78 (2H, m, CH2O), 5.35 (2H, m, CH2CH--), 6.05 (1H, m, CHCH2), 6.07 (1H, br. singlet, N--H), 7.40 (2H, d, Ph-H), 8.03 (2H, d, Ph-H).
Reaction SMILES: I[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>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.[Cu]I.C1COCC1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[C:7]([CH:8]=[O:9])=[CH:6][N:5]=1
Reactant: COc1cc(I)c(C=O)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C#C[Si](C)(C)C)c(C=O)cn1
Yield: 67 %

Procedure:
4-Iodo-6-methoxynicotinaldehyde (0.41 g, 1.6 mmoles), trimethylsilylacetylene (0.35 mL, 2.8 mmol), PdCl2(PPh3)2 (catalytic amount), CuI (catalytic amount), triethylamine (2 mL) and THF (10 mL) were stirred at 60° C. for 2 h. The volatiles were evaporated and the residue was taken up in water and extracted with ether. The organic phase was dried, filtered and concentrated. Purification by column chromatography with EtOAc-heptanes (1:3) as eluent gave 0.25 g (68% yield) of 6-methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[CH:4][C:5]([F:16])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[C:10]([CH3:15])=[N:9]2)[CH:7]=1.CCO[C:21]([S-:23])=[S:22].[K+].Cl>CN(C)C=O>[F:16][C:5]1[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[C:10]([CH3:15])=[N:9]2)=[CH:7][C:2]2[N:1]=[C:21]([SH:23])[S:22][C:3]=2[CH:4]=1
Reactant: CCOC(=S)[S-]
Reactant: Cc1nn(-c2cc(N)c(Br)cc2F)c(=O)n1C
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc3nc(S)sc3cc2F)c(=O)n1C
Temperature: 140 °C
Yield: 75 %

Procedure:
30 mL N,N-dimethylformamide was charged with 0.01 mol 1-(5-amino-4-bromo-2-fluorophenyl)-3,4-dimethyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred until it became clear. 0.02 mol potassium ethyl xanthogenate was added to the mixture in two portions. The mixture was refluxed at 140° C. for 6 h, cooled, and poured into 100 mL ice water slurry. The mixture was acidified with 6 mol/L hydrochloric acid, and a large amount of solid materials crushed out. The title compound was obtained in a 75% yield as a white solid after filtration.
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=CO
Solvent: O
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]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:20])[C:9](N2[C@H](C(C)C)COC2=O)=[O:10])=[CH:4][CH:3]=1.[OH:21]O.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH3:20])[C:9]([OH:10])=[O:21])=[CH:6][CH:7]=1
Reactant: OO
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)[C@H](C)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of (4R)-3-[(2R)-2-(4-fluorophenyl )propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (2.59 g, 9.28 mmol) in 160 mL THF/H2O (3:1) at 0° C., was added 30% H2O2 (8.4 mL, 74.2 mmol) followed by LiOH (780 mg, 18.6 mmol). The resulting mixture was stirred at 0° C. for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueous Na2SO3 (54 mL). After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 1.43 g (8.51 mmol, 92%) of (2R)-2-(4-fluorophenyl)propanoic acid; [α]D=−61.5° (C=1.04, MeOH): 1H NMR (400 MHz, CDCl3) δ 12.2–11.4 (br, 1H), 7.31–7.24 (m, 2H), 7.04–6.97 (m, 2H), 3.72 (q, 1H, J=7.3 Hz), 1.49 (d, 3H, J=7.3 Hz); ESMS m/e: 167.2 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](F)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([SH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CS(C)=O>[CH2:19]([S:26][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Cl:1])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(F)cc1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(SCc2ccccc2)cc1Cl
Temperature: 50 °C
Yield: 94.4 %

Procedure:
Methyl 2-chloro-4-fluorobenzoate (1.92 g, 10.2 mmol, 1 eq), cesium carbonate (3.74 g, 11.5 mmol, 0.13 eq) and benzyl mercaptan (1.3 g, 10.5 mmol, 1.03 eq) were combined in dimethyl sulphoxide (20 ml) and the reaction mixture heated at 50° C. for 4 hours. The reaction mixture was poured into ethyl acetate (10 ml) then washed with water (10 ml). The organic phase was dried over sodium sulphate, evaporated to yield the title compound as pink oil (2.82 g, 9.63 mmol, 95%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([F:15])[C:9]=2[F:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([F:15])[C:9]=2[F:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(F)c(F)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2ccc(F)c(F)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=383.3 (M+H+), was prepared in accordance with the general method of example 12b) from 6,7-difluoro-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.