Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH:25]2[CH2:29][CH2:28][N:27]([C:30]3[S:31][C:32]4[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:26]2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH:6]=1.SCC(O)=O.C1CCN2C(=NCCC2)CC1.CN(C)C=O>O>[CH3:1][O:2][C:3](=[O:40])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH:25]2[CH2:29][CH2:28][N:27]([C:30]3[S:31][C:32]4[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:26]2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(CN(C2CCN(c3nc4ccc(Cl)cc4s3)C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: O=C(O)CS
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(CNC2CCN(c3nc4ccc(Cl)cc4s3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A mixture of [3-[[[1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-yl]-(2-nitrobenzensulphonyl)amino]methyl]phenyl]acetic acid methyl ester (412 mg), mercaptoacetic acid (95 mL), 1,8-diazabicyclo[5,4,0]-7-undecene (4 mL) and dimethylformamide (4 mL) was stirred at room temperature for 1 hour. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (204 mg). Yield: 71%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:12][C:13](=[O:16])[CH2:14]Cl)([CH3:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.CC([O-])(C)C.[K+].CO>CC(O)(CC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:11])[NH:12][C:13](=[O:16])[CH2:14][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(CO)(NC(=O)CCl)c1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Solvent: CO
Product: CC1(c2cccc(Br)c2)COCC(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of (RS)—N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (5.36 g, 17 mmol) in 2-methyl-2-butanol (100 ml) was treated in one portion with potassium tert-butylate (6.66 g, 58 mmol). Initially, the temperature rose to 30° C.; the reaction mixture was left to cool to room temperature and stirring was continued for one hour. For the workup, the reaction mixture was treated with methanol (50 ml), then evaporated at reduced pressure. The residue was purified by chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 75/25 as the eluent. There were obtained 4.18 g (88% of theory) of (RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one as a white solid. MS (ISP): m/z=270.1 [M+H]+, 272.2 [M+2+H]+.
Reaction SMILES: [CH3:1]O.[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH2:1]=[CH:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:8]=[CH:3][CH:4]=[CH2:5].[CH2:1]=[CH:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CO
Reactant: Cc1ccccc1
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
In a 100-ml of toluene was dissolved 5 g of the polymer produced above. The resulting solution was subjected to high speed centrifugation at 10,000 rpm to separate it into a toluene-soluble portion (A) and a toluene-insoluble portion (I). The toluene-insoluble portion was 20.2% of the original polymer. Methanol was added in small portions to the toluene-soluble portion to precipitate part of the polymer of the toluene-soluble portion and thus Sample B was obtained. Then, a large amount of methanol was added to the residue to obtain Sample C. Thus, the toluene-soluble portion of the original polymer was subjected to fractional precipitation to obtain Samples B and C. Incidentally, the styrene-butadiene-styrene block copolymer produced in the first step of polymerization was named "Sample S".
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][N:55]([CH2:62][CH2:63]O)[C:56]1[CH:61]=[CH:60][N:59]=[N:58][CH:57]=1.Cl>C(Cl)Cl.C(Cl)Cl.CO>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:63][CH2:62][N:55]([CH3:54])[C:56]4[CH:61]=[CH:60][N:59]=[N:58][CH:57]=4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CN(CCO)c1ccnnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN(C)c1ccnnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (314 mg, 1.2 mmol) and 2-(N-methyl-N-(pyridazin-4-yl)amino)ethanol (80 mg, 0.52 mmol) in methylene chloride (5 ml) and the mixture stirred for 2 hours at ambient temperature. The solvent was removed by evaporation, the residue was triturated with ether and the resulting solid was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/methanol (9/1 followed by 8/2) to give a white solid. This solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (0.5 ml of a 4M solution) was added. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(pyridazin-4-yl)amino)ethoxy)quinazoline hydrochloride (110 mg, 60%). 1H NMR Spectrum: (DMSOd6) 3.11(s, 3H); 3.89(s, 3H); 3.94(t, 2H); 4.37(t, 2H); 6.85(dd, 1H); 7.21(s, 1H); 7.35(dd, 1H); 7.55(dd, 1H); 7.59(t, 1H); 7.8(s, 1H); 8.36(s, 1H); 8.59(d, 1H); 8.90(d, 1H); 9.57(s, 1H)
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C=O)C.CC[N:19]([CH:23]([CH3:25])[CH3:24])C(C)C.C1(N)CC1>O>[NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH:23]1[CH2:25][CH2:24]1)=[O:6]
Reactant: Nc1c(I)cccc1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(I)cccc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To 2-amino-3-iodo-benzoic acid (200 mg, 0.76 mmol) in DMF (1 mL) TBTU (244.15 mg, 0.76 mmol) and DIPEA (245.69 μL, 1.52 mmol) are added and stirred at r.t. for 7 min. Cyclopropylamine (52.69 μL, 0.76 mmol) is added and stirred at r.t. overnight. The reaction mixture is diluted with water and the precipitate is filtered off and dried.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([OH:12])=O)[C:7]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:25]=[N:24][N:23]([CH3:26])[C:22]=1[C:27]([N:29]1[CH2:32][CH2:31][CH2:30]1)=[O:28]>>[N:29]1([C:27]([C:22]2[N:23]([CH3:26])[N:24]=[CH:25][C:21]=2[NH:20][C:10]([C:8]2[C:7]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)=[O:12])=[O:28])[CH2:30][CH2:31][CH2:32]1
Reactant: Cn1ncc(N)c1C(=O)N1CCC1
Reactant: O=C(O)c1nc(C2CC2)cnc1Nc1cccnc1
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cccnc2)c1C(=O)N1CCC1

Procedure:
The product was obtained starting from 6-cyclopropyl-3-(pyridin-3-ylamino)pyrazine-2-carboxylic acid (30 mg, 0.12 mmol; example 217, step 2) and (4-amino-2-methyl-2H-pyrazol-3-yl)-azetidin-1-yl-methanone (27 mg, 0.15 mmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as light yellow solid (37 mg, 75%).
Reaction SMILES: FC1C=C(F)C=C[C:3]=1[C:9]1[CH:10]=[C:11]([CH2:20]O)[C:12](=O)N(CC(C)C)N=1.[F:22][C:23]1[CH:24]=[C:25]([C:31]2[CH:32]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34](=[O:37])[NH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C1(CBr)CCCC1>>[CH:11]1([CH2:12][N:35]2[C:34](=[O:37])[C:33]([C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([F:22])[CH:24]=3)=[N:36]2)[CH2:10][CH2:9][CH2:3][CH2:20]1
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Agent: BrCC1CCCC1
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC2CCCC2)c1=O
Yield: 72 %

Procedure:
Following the procedure of Example 1 (6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and cyclopentylmethyl bromide {J. Org. Chem., 36, 3103 (1971)} were reacted to yield the title compound as yellow needles (yield: 72.0%).
Reaction SMILES: [CH3:1][CH:2]1[CH:13]=[C:12]([CH3:14])[CH2:11][CH2:10][C:3]21[C:7](=[O:8])[O:6][C:5](=O)[CH2:4]2.[CH2:15]([Mg]Cl)[CH3:16].Cl.[C:20]1(C)C=CC=C[CH:21]=1>O1CCCC1>[CH2:20]([C:5]1([CH2:15][CH3:16])[CH2:4][C:3]2([CH2:10][CH2:11][C:12]([CH3:14])=[CH:13][CH:2]2[CH3:1])[C:7](=[O:8])[O:6]1)[CH3:21]
Reactant: CC[Mg]Cl
Reactant: CC1=CC(C)C2(CC1)CC(=O)OC2=O
Reactant: Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCC1(CC)CC2(CCC(C)=CC2C)C(=O)O1

Procedure:
6,8-Dimethyl-2-oxa-spiro[4.5]dec-7-ene-1,3-dione (prepared as above in EXAMPLE I, 140 g) was fed slowly into an ethyl magnesium chloride (C2H5MgCl) solution in tetrahydrofuran (THF) (2 M, 1.53 L) while the temperature was kept under 25° C. After the feeding was completed, the reaction was aged at room temperature for about an hour. The reaction mixture was then poured into hydrochloric acid (HCl) (2 M) containing ice. Toluene was added. The organic and aqueous layers were shaken in a separatory funnel and separated. The aqueous layer was further washed with toluene. The organic layers were combined and washed with sodium carbonate (Na2CO3) solution until basic. The resulting solution was distilled to afford 3,3-diethyl-6,8-dimethyl-2-oxa-spiro[4.5]dec-7-en-1-one (170 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:21]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH2:21]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3]([S:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)c2ccccc2I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 84.9 %

Procedure:
A mixture of 4-nitrophenyl 2-iodobenzenesulphonate (0.405 g), 4-isobutylphenylboronic acid (obtained as described in European Patent Application, publication No. 0569193) (0.179 g), tetrakis(triphenylphosphine)palladium(0) (0.058 g), toluene (15 ml), ethanol (10 ml) and 2M sodium carbonate solution (5.5 ml) was stirred vigorously and heated under reflux for 5 hours. Water (20 ml) was added and the mixture was extracted with ethyl acetate (2×25 ml). The combined extracts were washed with saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by elution with ethyl acetate/hexane (1:3 v/v) through a silica gel Mega Bond Elut column to give 4-nitrophenyl 4'-isobutyl-2-biphenylsulphonate (0.349 g); 1H NMR (d6 -DMSO): 0.9 (d,6H), 1.8-2.0 (m,1H), 2.5 (d,2H), 7.1-7.25 (m,4H), 7.35 (d,2H), 7.55 (d,1H), 7.7 (t,1H), 7.9 (t,1H), 8.05 (d,1H), 8.2 (d,2H); mass spectrum (+ve FAB, DMSO/methanol/NBA): 412 (H+H)+.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:18][C:19]1[C:23](C#N)=[C:22]([CH2:26][CH3:27])[NH:21][N:20]=1>C(O)(=O)C>[CH2:26]([C:22]1[C:23]([C:19]#[N:18])=[C:17]2[N:2]=[CH:3][CH:4]=[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=3)[N:20]2[N:21]=1)[CH3:27]
Reactant: CCc1[nH]nc(N)c1C#N
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: CCc1nn2c(-c3cccc(C(F)(F)F)c3)ccnc2c1C#N

Procedure:
A mixture of 7.29 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone and 4.08 g. of 3-amino-5-ethylpyrazole-4-carbonitrile in 25 ml. of glacial acetic acid is refluxed for 15 hours and then evaporated to a residue. This residue is treated as described in Example 1, giving the desired product, m.p. 144°-146° C.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+]>O>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: [NH4+]
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
A batch type process wherein the catalyst compositions are stirred in from 0.1 to 5.0 molar (preferably 0.5 to 2.0 molar) solutions of ammonium fumarate in water at 5.0 to 10.0 pH (preferably 7.5 to 9.5 pH) for periods of 1.0 to 100 hours (preferably 8 to 48 hours) at temperatures below 50° C. (preferably 20° to 40° C.). Broadly from 0.05 to 50 g of immobilized cells, preferably from 1.0 to 15 g, are used per 1.0 mole of starting ammonium fumarate. After the conversion, the catalyst compositions may be removed by filtration or the equivalent for reuse in converting fresh batches of fumarate solutions. The product solutions are obtained in a form suitable for conventional processing to isolate the L-aspartic acid (acidification, precipitation, filtration, washing, recrystallization, drying).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][OH:29]>>[OH:29][CH2:28][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: OCCBr
Reactant: COc1ccc(COC(=O)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(COC(=O)c2ccc(OCCO)cc2)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 4-methoxybenzyl 4-hydroxybenzoate (7.0 g, 27 mmole) in dry N,N-dimethylforuiamide (50 ml) was added potassium carbonate (4.15 g, 30 mmole) and 2-bromoethanol. The mixture was stirred 48 hours at 80° C., evaporated under reduced pressure and ethyl acetate and water were added. The organic phase was washed five times with water and dried with sodium sulfate. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography with hexane/ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=O.[CH3:18][C:19]([S:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[N:24][S:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23]
Reactant: CC(C)(C)S(N)=O
Reactant: Nc1ccc(Br)cc1C(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C(c1ccc(Cl)cc1)c1cc(Br)ccc1N
Temperature: 80 °C

Procedure:
To a solution of (2-Amino-5-bromo-phenyl)-(4-chloro-phenyl)-methanone (13.87 g, 0.05 mol) in THF (200 mL) is added 2-Methyl-propane-2-sulfinic acid amide (6.5 g, 0.05 mol) and Ti(OEt)4 (20.5 g, 0.09 mol).The stirred mixture is refluxed at 80° C. The mixture is quenched with H2O, filtered. THF is removed, extracted with ethyl acetate, dried over NaSO4 and concentrated then purified by silica gel. This produces the desired compound.
Reaction SMILES: [CH2:1]1[CH2:12][C:10](=[O:11])[C:4]2[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:3]=2[CH2:2]1.Cl.[CH3:14][NH:15][CH3:16].[CH2:17]=O.Cl>CC(C)=O.C(O)C>[ClH:9].[Cl:9][C:6]1[CH:5]=[C:4]2[C:3]([CH2:2][CH2:1][CH:12]([CH2:14][N:15]([CH3:17])[CH3:16])[C:10]2=[O:11])=[CH:8][CH:7]=1
Reactant: C=O
Reactant: O=C1CCCc2ccc(Cl)cc21
Reactant: CNC
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: CN(C)CC1CCc2ccc(Cl)cc2C1=O
Yield: 94 %

Procedure:
7-Chloro-α-tetralone (15.0 g), 8.75 g of dimethylamine hydrochloride, 3.25 g of paraformaldehyde, and 17.5 ml of 95% ethanol containing 0.2 ml of concentrated hydrogen chloride are combined and heated on a steam bath for 2 hours. The warm solution is transferred to a wide-mouthed flask, diluted with 200 ml of acetone, and allowed to stand at room temperature for several hours. The resultant crystals are collected and crystallized from acetone/ethanol to give 10.7 g of the title compound, melting point 169°-170° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.Br[CH2:18][CH2:19]Br>>[N:16]1[CH:15]=[CH:14][N:13]2[C:12]=1[C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[O:1][CH2:19][CH2:18]2
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)c(-c2ncc[nH]2)c1
Product: COC(=O)c1ccc2c(c1)-c1nccn1CCO2
Yield: 76 %

Procedure:
Following the procedure in Example 17, methyl 4-hydroxy-3-(1H-imidazol-2-yl)benzoate reacted with 1,2-dibromoethane to give methyl 5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate. Yield 76%. MS(ESI+): 245.0. 1H NMR (400 MHz, CDCl3) δ 9.21 (d, J=2.2, 1H), 7.91 (dd, J=8.6, 2.2, 1H), 7.20 (t, J=4.8, 1H), 7.05 (d, J=8.6, 1H), 7.00 (d, J=0.8, 1H), 4.53-4.48 (m, 2H), 4.43-4.39 (m, 2H), 3.91 (d, J=5.9, 3H).
Reaction SMILES: C[O:2][C:3]([C@@:5]12[CH2:23][C@H:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[N:13]1[C@@H:8]([CH2:9][C@@H:10]([O:26][C:27]3[CH:32]=[C:31]([C:33]4[S:34][CH:35]=[C:36]([CH3:38])[N:37]=4)[N:30]=[C:29]([C:39]4[S:40][CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[N:43]=4)[N:28]=3)[CH2:11][CH2:12]1)[C:7](=[O:48])[NH:6]2)=[O:4].C(C1N=C(C2C=C(O[C@H]3C[C@@H]4N(C(=O)N(C)CCCCC=C[C@H]5[C@](C(O)=O)(NC4=O)C5)CC3)C3C(=C(C)C(OC)=CC=3)N=2)SC=1)#C>>[CH3:38][C:36]1[N:37]=[C:33]([C:31]2[N:30]=[C:29]([C:39]3[S:40][CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[N:43]=3)[N:28]=[C:27]([O:26][C@@H:10]3[CH2:9][C@@H:8]4[N:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][C@H:22]5[C@:5]([C:3]([OH:4])=[O:2])([NH:6][C:7]4=[O:48])[CH2:23]5)[CH2:12][CH2:11]3)[CH:32]=2)[S:34][CH:35]=1
Reactant: COC(=O)[C@@]12C[C@H]1C=CCCCCN(C)C(=O)N1CC[C@H](Oc3cc(-c4nc(C)cs4)nc(-c4nc(C(F)(F)F)cs4)n3)C[C@H]1C(=O)N2
Agent: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Product: Cc1csc(-c2cc(O[C@H]3CCN4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@H]4C3)nc(-c3nc(C(F)(F)F)cs3)n2)n1
Yield: 82 %

Procedure:
(1S,4R,6S,18S)-18 [6-(4-Methylthiazol-2-yl)-2-(4-trifluoromethylthiazol-2-yl)-pyrimidin-4-yloxy]-13-N-methyl-2,14-dioxo-3,13,15-triazatricyclo[13.4.0.0*4,6*]nonadec-7-ene-4-carboxylic acid 42b was synthesized from compound 41b (250 mg, 1.0 eq.), according to the procedure as described for compound 38, as a green foam in 82% yield. MS (ESI, EI−) m/z=690 (MH−).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:26])[C:10]2[O:16][C:15]3[C:17]([Cl:22])=[CH:18][C:19]([NH2:21])=[CH:20][C:14]=3[CH2:13][S:12](=[O:24])(=[O:23])[C:11]=2[CH:25]=1)=[O:6]>O.CO>[NH2:21][C:19]1[CH:18]=[C:17]([Cl:22])[C:15]2[O:16][C:10]3[C:9]([CH3:26])=[CH:8][C:7]([C:5]([OH:6])=[O:4])=[CH:25][C:11]=3[S:12](=[O:23])(=[O:24])[CH2:13][C:14]=2[CH:20]=1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A solution of sodium hydroxide (0.32 g, 7.13 mmol) in water (5 mL) was added to a solution of Example 1 (1 g, 2.71 mmol) in methanol (30 mL). The reaction mixture was stirred at 60° C. for 1.5 h, the solvent was removed under vacuum and water (20 mL) was added. The reaction mixture was acidified to pH 3 using 10% aqueous hydrochloric acid. The precipitate was filtered and washed with water, dried to obtain the title compound. Yield: 0.85 g, (89%); 1H NMR (DMSO-d6, 300 MHz): δ 2.61 (s, 3H, CH3), 5.66 (s, 2H, CH2), 6.64 (d, 2H, Ar), 8.03 (s, 1H, Ar), 8.12 (s, 1H, Ar); MS: m/e (ES−) 352 (M−1).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[N:3]1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>CCOC(C)=O.CCCCCCC>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][N:2]([O:1][C:17](=[O:18])[N:16]([CH3:15])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:3]=2)=[CH:8][CH:9]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: COc1ccc(-c2ccn(O)n2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccn(OC(=O)N(C)c3ccccc3)n2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(4-methoxyphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, EtOAc-heptane) (93%, oil). HPLC-MS m/z=346.1 (M+Na), Rt: 4.21 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]#[N:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>CCCCCC.CS(C)=O>[C:4]1([CH:3]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10]#[N:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CCc1ccccc1
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Sodium hydride (2.2 g of 50% w/w slurry in mineral oil, 47.0 mmol) was washed with hexane and dried under vacuum. Dimethylsulfoxide (40 mL) was added, and the mixture was stirred and cooled in an ice bath while a solution of benzyl cyanide (5.0 g, 42.7 mmol) in dimethyl-sulfoxide (10 mL) was added dropwise. The ice bath was removed, and the solution was allowed to stir for 4 hours. The deep red solution was then cooled again to 0° C., and a solution of 1-iodopentane (5.60 mL, 42.7 mmol) in dimethyl-sulfoxide (10 mL) was added dropwise. The mixture was stirred and allowed to come to ambient temperature over 12 hours. It was poured into water (200 mL), and extracted with ethyl acetate (2×200 mL). The extracts were washed in sequence with water (3×200 mL), then combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The oily residue was separated by column chromatography (3:97 ethyl acetate-hexane) to afford the product, 2-phenylheptanenitrile, as a clear oil (4.41 g, 23.5 mmol, 55%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cc(N)ncn2)c1
Temperature: 125 °C
Yield: 69.6 %

Procedure:
A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), 3-methoxyphenylboronic acid (0.475 g, 3.13 mmol), Na2CO3 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspended in DME/EtOH/water (15:2:3 mL), heated in the microwave synthesizer at 125° C. for 20 min and concentrated. The residue was purified by silica gel chromatography (10-60% ethyl acetate-hexanes) to afford 6-(3-methoxyphenyl)pyrimidin-4-amine (0.35 g, 1.74 mmol, 70% yield) as an off-white solid. LCMS R.T.=1.28; [M+H]+=201.98.