Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([CH:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]2=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:51][N:52]1[CH2:56][C@H:55]([SH:57])[CH2:54][C:53]1=[S:58].P([O-])([O-])([O-])=O>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]=2[S:57][C@H:55]2[CH2:56][N:52]([CH3:51])[C:53](=[S:58])[CH2:54]2)=[O:11])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: CN1C[C@H](S)CC1=S
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CC(=S)N(C)C3)[C@H](C)[C@H]12
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
(1R, 5R, 6S)-6-[(1R)-1-Hydroxyethyl]-1-methyl-2- oxocarbapenam-3-carboxylic acid 4-nitrobenzyl ester (25.2 g) is dissolved in anhydrous acetonitrile (173 ml), and thereto are added dropwise diisopropylethylamine (13 ml) and diphenylphosphoryl chloride (15.5 ml) in this order under nitrogen gas below 0° C. After stirring the mixture at the same temperature for 30 minutes, a solution of (4R)-N-methyl-4- mercaptopyrrolidine-2-thione (13 g) and diisopropylethylamine (11.5 g) in anhydrous acetonitrile (173 ml) is added dropwise to the reaction mixture below -5° C. After stirring the mixture at 0° C. for 1.5 hour, the reaction mixture is poured into phosphate buffer (pH 7.0, one liter). The precipitated crystal is separated by filtration and dissolved in a mixture of chloroform (2 liters) and tetrahydrofuran (1 liter), and the solution is washed with water, dried and concentrated to dryness under reduced pressure. The residue is crystallized from diethyl ether to give (1R, 5S, 6S)-2-[(4R)-N-methyl- pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen -2-em-3-carboxylic acid 4-nitrobenzyl ester (23.5 g) as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[CH:14][C:15](=[O:17])[CH3:16])[CH:7]=[CH:6]2.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[CH:7]=[CH:6]2
Reactant: [H][H]
Reactant: COc1ccc2cc(C=CC(C)=O)ccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2cc(CCC(C)=O)ccc2c1
Yield: 69.7 %

Procedure:
4-(6-Methoxy-2-naphthyl)-3-butene-2-one (32 g) in ethyl acetate (500 ml) was shaken at room temperature over 10% Pd/C (3 g) under atmospheric pressure hydrogen until no further uptake of hydrogen occurred to yield 4-(6-methoxy-2-naphthyl)butan-2-one (22.5 g), mp. 78.5° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1.[Br:32]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(OCC)(=O)C>[Br:32][C:14]1[C:13]2[C:9](=[CH:10][N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=3)[N:12]=2)[CH:8]=[CH:7][C:6]=1[O:5][CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)(C(C)C)C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)c(Br)c3n2)cc1)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2H-indazole (1.31 g) in ethyl acetate (15 mL) were added N-bromosuccinimide (0.56 g) and azobisisobutyronitrile (99 mg), and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as an orange oil (1.41 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Cl.[C:11]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH2:19])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:19][CH2:18][CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:20])=[N:3][CH:4]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCNc1ccc(C#N)cn1
Reaction time: 24 h

Procedure:
A solution of 6-chloronicotinonitrile (1.0 g, 7.2 mmol), beta-alanine tert-butyl ester hydrochloride (2.0 g, 11.0 mmol) and DIEA (4.9 mL, 28.9 mmol) in anhydrous dioxane (20 mL) was heated at reflux. After 24 hours, an additional amount of beta-alanine tert-butyl ester hydrochloride (0.5 g, 2.75 mmol) was added. After 24 additional hours at reflux, the reaction mixture was concentrated under reduced pressure. The residue was taken up with EtOAc (50 mL) and washed with water (2×20 mL) and brine (20 mL). The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. After precipitation from MTBE/pentane, the title compound was obtained as an off-white powder (1.28 g, 72%). HPLC (Method A), Rt: 2.7 min (purity: 99.9%). UPLC/MS, M+(ESI): 248.1, M−(ESI): 246.2. 1H NMR (DMSO-d6, 300 MHz) δ 8.40 (d, J=2.0 Hz, 1H), 7.67 (m, 2H), 6.56 (d, J=8.9 Hz, 1H), 3.50 (td, J=6.8, 6.0 Hz, 2H), 2.48 (t, J=6.8 Hz, 2H), 1.38 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([OH:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[OH:16].[CH3:17][N:18]=[C:19]=[O:20]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:14][O:13][C:12]1[C:3]([O:2][CH3:1])=[C:4]([O:16][C:19](=[O:20])[NH:18][CH3:17])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]=1[O:15][C:19](=[O:20])[NH:18][CH3:17]
Reactant: CN=C=O
Reactant: COc1c(OC)c(O)c2ccccc2c1O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CNC(=O)Oc1c(OC)c(OC)c(OC(=O)NC)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.00 g of 2,3-dimethoxy-1,4-dihydroxynaphthalene, prepared as shown in Preparation 5, in 50 ml of tetrahydrofuran was added 0.670 g of methyl isocyanate followed by 0.12 g of 4-dimethylaminopyridine. The solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate, washed with dilute hydrochloric acid and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue chromotographed on silica gel, eluting with methylene chloride, giving 2,3-dimethoxy-1,4-di(methylcarbamoyloxy)naphthalene, m.p. 228°-229° C.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[N:10]=[C:9](Cl)[CH:8]=[C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:6]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:8]=[C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:6]=1
Reactant: CC(C)(C)CNc1nc(Cl)cc(N2CCCC2)n1
Reactant: C1CNCCN1
Product: CC(C)(C)CNc1nc(N2CCCC2)cc(N2CCNCC2)n1
Yield: 76 %

Procedure:
(2,2-Dimethylpropylamino)-4-chloro-6-pyrrolidinopyrimidine is reacted with piperazine as described in Example 5 to obtain the title compound in a yield of 76%, m.p.:118°-120° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH:11]([CH:16]=[N:17][OH:18])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][C:25]#[CH:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][C:25]1[O:18][N:17]=[C:16]([CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:19])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:26]=1
Reactant: CC(C)CC(C=NO)NC(=O)OCc1ccccc1
Reactant: C#CCCC(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cc(C(CC(C)C)NC(=O)OCc2ccccc2)no1
Yield: 29.4 %

Procedure:
To a stirred solution of [1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid benzyl ester (6.0 g, 22.7 mmol) and pent-4-ynoic acid methyl ester (3.8 g, 34 mmol) in CH2Cl2 (80 ml) was added triethylamine (0.2 ml) followed by Clorox bleach (80 ml). After 4 h at room temperature the organic phase was separated and the aqueous phase was extracted with CH2Cl2 (25 ml×3). The combined organics were dried over MgSO4; filtered and concentrated under reduced pressure to give a yellow oil. Purification by Flash 40 chromatography using a silica gel column and eluting with 10-20% EtOAc/hexane gave 2.5 g of the title compound as a waxy pale yellow solid. MS [M+1]+375.3; 1H nmr (400 MHz, CDCl3) δ0.91 (m, 6H), 1.51-1.76 (m, 3H), 2.67 (t, J=7.5 Hz, 2H), 3.02 (t, J=7.5 Hz, 2H), 3.67 (s, 3H), 4.89 (m,1H), 5.08 (m, 3H), 5.92 (s, 1H), 7.31 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([NH2:11])=[O:10])[CH:4]=1.Cl[C:15]([S:17]Cl)=[O:16]>C(OCC)(=O)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[O:10][C:15](=[O:16])[S:17][N:11]=2)[CH:4]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: O=c1oc(-c2cccc(C(F)(F)F)c2)ns1
Yield: 86.3 %

Procedure:
α,α,α-Trifluoro-m-toluamide (82.7 g, 0.437 mol) and chlorocarbonylsulfenyl chloride (86 g, 0.667 mol, 53% excess) were reacted under the conditions of Example 2 for 0.5 hours. The light yellow residue was dissolved in ethyl acetate and cooled to -78°. The white precipitate was filtered and washed with hexane to yield 93.14 g (0.377 mol, 86.2%) of white solid, m.p. 85°-86.5°.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[CH2:14]([O:16][C:17](=[O:36])[C@H:18]([CH3:35])[CH2:19][C@H:20]([NH2:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH3:15]>C(Cl)Cl>[CH2:14]([O:16][C:17](=[O:36])[C@H:18]([CH3:35])[CH2:19][C@H:20]([N:34]=[C:2]=[O:4])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)[CH3:15]
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)N=C=O
Reaction time: 0.25 h

Procedure:
To a vigorously stirred 1:1 mixture of methylene chloride/8% aqueous NaHCO3 (30 mL) at 0° C. is added triphosgene (114 mg, 0.384 mmol). After stirring the mixture at 0° C. for 5 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (400 mg, 1.15 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester (1.15 mmol) in methylene chloride (10 mL) is added (S)-pyrrolidine-2-carboxylic acid methyl ester (1.15 mmol) and diisopropylethylamine (2.3 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is washed with aqueous 1M HCl and the organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using hexane/methylene chloride to elute the product.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:25]([CH3:30])([C:26]([NH:28]N)=[O:27])[C:24](=[O:31])[NH:23][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:9]=2)[N:7]=1.FC(F)(F)C(O)=O.N(OC(C)(C)C)=O.N[C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>C1COCC1>[NH2:1][C:2]1[C:3]2[C:25]([CH3:30])([C:26]([NH:28][C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)=[O:27])[C:24](=[O:31])[NH:23][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:22])([F:20])[F:21])[N:9]=2)[N:7]=1
Reactant: CC1(C(=O)NN)C(=O)Nc2nc(-c3nn(CCC(F)(F)F)c4ncccc34)nc(N)c21
Reactant: Nc1cccnc1
Agent: CC(C)(C)ON=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1(C(=O)Nc2cccnc2)C(=O)Nc2nc(-c3nn(CCC(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a THF solution (2 mL) of the intermediate from Step A (227 mg, 0.521 mmol) at 0° C. was added trifluoroacetic acid (0.044 mL, 0.574 mmol) and tert-butyl nitrite (0.186 mL, 1.564 mmol). After stirring at 0° C. for 30 minutes, the mixture was concentrated in vacuo, ensuring that the temperature was maintained below 40° C. The residue was suspended in acetonitrile (3 mL), cooled to 0° C., and 3-aminopyridine (245 mg, 2.61 mmol) was added in one portion. The resultant mixture was heated to 40° C. for one hour, and then stirred at ambient temperature for 16 hours. The mixture was concentrated in vacuo, suspended in EtOAc and washed sequentially with water (4×), saturated aqueous ammonium chloride solution (2×), and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography using DCM/MeOH (with 0.5% NH4OH) gradient provided the title compound. Chiral separation using SFC on a Chiralpak IC column provided both enantiomers of the title compound, 1H NMR (500 MHz, DMSO-d6): δ 9.53 (1H, s), 9.05 (1H, dd, J=8.08, 1.58 Hz), 8.77 (1H, d, J=2.48 Hz), 8.63 (1H, dd, J=4.47, 1.58 Hz), 8.28 (1H, d, J=4.69 Hz), 8.00 (1H, d, J=8.47 Hz), 7.36 (2H, ddd, J=21.65, 8.21, 4.57 Hz), 6.86 (2H, s), 4.85-4.77 (2H, m), 3.06-2.95 (2H, m), 1.72 (3H, s). m/z=498.2 (M+H).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[CH:11]=3)[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:15])([CH3:16])[C:12](=[O:17])[C:11]=3[Br:25])[CH:7]=[CH:6][C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(c2ccc3nonc3c2)=CC1=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)OC(c2ccc3nonc3c2)=C(Br)C1=O
Reaction time: 3 h
Yield: 59.6 %

Procedure:
To a stirred solution of 5-(benzo[c][1,2,5]oxadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.25 g, 1.086 mmol) in CHCl3 (15 mL), NBS (0.29 g, 1.630 mmol) was added portionwise at RT. The reaction mixture was then stirred for 3 h and diluted with DCM (10 mL). The organic layer was then washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(benzo[c][1,2,5]oxadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.2 g, 60%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10]C)=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH:12]=[O:13].P(Br)(Br)Br>ClCCl>[OH:1][C:2]1[C:9]([OH:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH:12]=[O:13]
Reactant: COc1cc(C=O)cc(C=O)c1O
Agent: BrP(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(C=O)c1
Temperature: 0 °C

Procedure:
To a suspension containing 1.8 g of 4-hydroxy-5-methoxy-isophthalaldehyde in 20 ml of dichloromethane was added 35 ml of 1 molar PBr3 in dichloromethane. The mixture was allowed to stand over night at room temperature and poured into ice-water. Dichloromethane was evaporated in vacuo. After cooling the product was filtered and washed with water. Yield 0.94 g (57%), m.p. 192°-195° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH2:13].[C:14]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:15][CH:16]=1)=[O:21]
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(F)cc12)c1ccc(-c2ccccc2)cc1
Yield: 75.6 %

Procedure:
N-(2-(5-Fluoro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtained following Method C starting from 2-(5-fluoro-1H-indol-3-yl)ethanamine (0.100 g, 0.561 mmol), biphenyl-4-carbonyl chloride (0.130 g; 0.589 mmol), and triethylamine (0.095 mL; 0.673 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.152 g (76%) of N-(2-(5-Fluoro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:8]=1.Cl.Cl.N1C2C(=NC=CC=2OC2C=CC(N[C:43]([NH:45][C:46](=[O:56])[CH2:47][C:48]3[C:53](Cl)=[CH:52][CH:51]=[CH:50][C:49]=3Cl)=[S:44])=CC=2F)C=C1.ClC1C=CC=C(Cl)C=1CC(N=C=S)=O.[N-]=C=S>>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:43]([NH:45][C:46](=[O:56])[CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[S:44])=[CH:19][CH:18]=2)[CH:8]=1
Reactant: Cn1ccnc1-c1cc2nccc(Nc3ccc(N)cc3)c2s1
Reactant: O=C(Cc1c(Cl)cccc1Cl)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Agent: Cl
Agent: O=C(Cc1c(Cl)cccc1Cl)N=C=S
Agent: [N-]=C=S
Product: Cn1ccnc1-c1cc2nccc(Nc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)c2s1
Yield: 12 %

Procedure:
Starting from the compound 301, following the procedures described above for the synthesis of compound 269b (scheme 61, example 222) but replacing 2-(2,6-dichlorophenyl)acetyl isothiocyanate with 2-phenylacethyl isothiocyanate, title compound 302 was obtained in 12% yield, as a yellow solid. 1H NMR (d-DMSO) δ (ppm): 12.47(s, 1H), 11.76(s, 1H), 10.83(s, 1H), 8.41(d, 1H, J=6.9 Hz), 7.84(s, 1H), 7.80(s, 1H), 7.78(s, 1H), 7.55(s, 1H), 7.46(s, 1H), 7.43(s, 1H), 7.32(m, 4H), 7.28-7.20(m, 1H), 7.20(s, 1H), 6.94(d, 1H, J=6.8 Hz), 3.98(s, 3H), 3.81(s, 2H). MS (m/z): 499.1(M+H) (found).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CO.[CH3:13][NH2:14]>C(O)C>[CH3:13][NH:14][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: CN
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CO
Solvent: CCO
Product: CNc1ncnc2[nH]cnc12
Temperature: 120 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
In 20 mL of a 40% methylamine methanol solution and 20 mL of ethanol, 12.5 g (79 mmol) of 6-chloropurin was dissolved and the solution was sealed in a tube and stirred in the tube at 120° C. for four hours. The reaction solution was concentrated, and then triturated with water and collected on a filter, washed with water, and then vacuum dried to obtain 10.78 g (90%) of methyl-(9H-purin-6-yl)amine as a white solid.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[I:25]I.Cl>CCCCCC.C1COCC1>[CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([F:19])[C:15]([I:25])=[C:16]([F:18])[CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CCC(c2cc(F)cc(F)c2)CC1
Reactant: II
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC1CCC(c2cc(F)c(I)c(F)c2)CC1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a mixture of (4-pentyl-cyclohexyl)-3,5-difluorobenzene (10 mmol) and 150 ml of THF, was added dropwise 7.5 ml of a solution of n-butyl lithium (corresponding to 12 mmol) in hexane while keeping them at a temperature lower than −70° C., and stirred at the same temperature for 30 min. While keeping the solution at a temperature lower than −70° C., iodine (30 mmol) was added thereto. Then, the solution was stirred for 1.5 hours, temperature of the solution was gradually backed up to room temperature, and then the solution was stirred for 2 hours. After 12 ml of 1N hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted once with toluene and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: heptane) to give a (4-pentyl-cyclohexyl)-3,5-difluoro-4-iodobenzene (8.3 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].Cl[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9].Cl>[OH-].[Na+]>[CH2:11]([O:10][C:8]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: NCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOC(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
20 g (224.46 mmol) of β-alanine were dissolved in 225 ml of 1N sodium hydroxide solution. 44 ml of octyl chloroformate were then added dropwise, while keeping the pH of the reaction medium above 9 by simultaneous addition of one molar equivalent of 1N sodium hydroxide. After stirring for 6 hours at room temperature, the mixture was acidified with about 1.1 molar equivalents of 3N hydrochloric acid solution. The heterogeneous mixture was extracted with 300 ml of ethyl acetate. The organic phase was washed with 3 times 80 ml of water, dried and then evaporated to dryness. The solid residue was taken up in heptane and then filtered and dried. 51 g of a white product were obtained (yield of 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][C:22]=1[Cl:31])(=[O:19])[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[C:22]([Cl:31])[CH:23]=1)(=[O:28])=[O:29])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1Cl
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1Cl

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 133 mg of 4-acetylamino-3-chloro-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.24 (s, 3H), 7.36 (d, 1H, J=2.4), 7.40–7.60(m, 8H), 7.66 (d, 1H, J=2.0 Hz), 7.71 (d, 1H, J=8.8 Hz), 8.36 (d, 1H, J=8.8 Hz), 9.63 (s, 1H). MS: m/z 463.0 (M++1).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:16]1[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=1)[CH2:10][CH2:9]2.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:18])[C@@:3]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:27](=[O:28])[C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:30])([F:19])[F:31])=[CH:26][N:25]=4)[CH:15]=3)[CH2:10][CH2:9]2)[N:4]=1
Reactant: NC1=N[C@@]2(CCc3ccc(N)cc32)C(F)(F)CO1
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Product: NC1=N[C@@]2(CCc3ccc(NC(=O)c4ccc(C(F)(F)F)cn4)cc32)C(F)(F)CO1
Yield: 15 %

Procedure:
The condensation of (R)-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazine]-2′,6-diamine (intermediate A7.3) and 5-(trifluoromethyl)picolinic acid yielded the title compound (15% yield) as an off-white solid. MS (ISP): m/z=427.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22]SC)[CH:5]=1)([O-:3])=[O:2].C[I:26]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22][I:26])[CH:5]=1)([O-:3])=[O:2]
Reactant: CSCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Reactant: CI
Product: O=C1c2ccc(Cl)cc2C(=O)N1c1ccc([N+](=O)[O-])cc1CI

Procedure:
The mixture of 1.5 g of N-(4-nitro-2-methylmercaptomethylphenyl)-4-chlorophthalimide and 50 ml of methyl iodide is refluxed for 6 days in the absence of light and evaporated. The residue is taken up in hot benzene, the mixture filtered and evaporated to yield the N-(4-nitro-2-iodomethylphenyl)-4-chlorophthalimide melting at 183°-187°.