Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:14]=[CH:13][C:12]=2[CH2:11]1.[C:27]([O:30][CH2:31][CH2:32]Br)(=[O:29])[CH3:28].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:31]([O:30][C:27]([CH2:28][NH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:25])[CH3:24])[CH:14]=[CH:13][C:12]=2[CH2:11]1)=[O:29])[CH3:32]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N)c1
Reactant: CC(=O)OCCBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Yield: 60.7 %

Procedure:
A mixture of pivalic acid 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (110 mg), bromoethyl acetate (400 mg), sodium acetate (200 mg) and ethanol (2 ml) was refluxed overnight. A saturated aqueous solution of sodium bicarbonate was added, and the solution was extracted with ethyl acetate. The solution was washed with brine, dried over magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (83 mg).
Reaction SMILES: [CH3:1][S:2](O)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[S:14]([NH2:17])(=[O:16])=[O:15].N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][C:8]=1[S:14]([NH2:17])(=[O:15])=[O:16]
Reactant: CS(=O)(=O)O
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 23 °C
Reaction time: 20 h
Yield: 86.3 %

Procedure:
2,5-Diamino-benzenesulfonamide methanesulfonate (1.80 kg, 6.35 mol) was suspended in acetonitrile (24 L). Pyridine (1.55 L, 19.1 mol) was added, followed by the careful slow addition of methanesulfonyl chloride (517 mL, 6.68 mol). After stirring at 23° C. for 20 h, the mixture was partially concentrated in vacuo at 55° C. Water (18 L) was added to the concentrate, and the resulting suspension was stirred at 23° C. for 2 h. The solid was filtered and was then washed with water (4 L) and air dried on the filter. The solid was suspended in absolute ethanol (9 L), stirred at 23° C. for 9 h, and was then filtered. The solid was washed with absolute ethanol (2×2 L), and was then further dried in vacuo at 50° C. to afford the desired product, 2-amino-5-methanesulfonylamino-benzenesulfonamide (1.45 kg, 5.48 mol, 86%), as a purple solid.
Reaction SMILES: ClC1C=CC(CCl)=CN=1.COC(=O)COC1C=C(OC)C(S)=CC=1C.C[O:27][C:28](=[O:58])[CH2:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([S:39][CH2:40][C:41]2[CH:42]=[N:43][C:44]([C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=3)=[CH:45][CH:46]=2)=[CH:33][C:32]=1[CH3:57]>>[CH3:38][O:37][C:35]1[C:34]([S:39][CH2:40][C:41]2[CH:42]=[N:43][C:44]([C:47]3[CH:48]=[CH:49][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:51][CH:52]=3)=[CH:45][CH:46]=2)=[CH:33][C:32]([CH3:57])=[C:31]([CH:36]=1)[O:30][CH2:29][C:28]([OH:58])=[O:27]
Reactant: COC(=O)COc1cc(OC)c(SCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1C
Agent: COC(=O)COc1cc(OC)c(S)cc1C
Agent: ClCc1ccc(Cl)nc1
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared from 2-Chloro-5-chloromethyl-pyridine and 1D in a manner analogous to Example 1F. MS m/z 370 (M+2). Step 2. Preparation of {5-Methoxy-2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethylsulfanyl]-phenoxy}-acetic acid methyl ester (Compound 19B)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH:11]([CH3:30])[C:12]([OH:29])([C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1)[C:13]([F:16])([F:15])[F:14].[CH3:31][O:32][C:33](=[O:41])[CH2:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:31][O:32][C:33](=[O:41])[CH2:34][CH:35]1[CH2:36][CH2:37][N:38]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([CH:11]([CH3:30])[C:12]([OH:29])([C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=4[CH:28]=3)[C:13]([F:15])([F:14])[F:16])[CH:4]=2)[CH2:39][CH2:40]1
Reactant: COC(=O)CC1CCNCC1
Reactant: CC(c1cc(C(=O)O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1CCN(C(=O)c2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
To a solution of 4-chloro-3-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-benzoic acid (74 mg) in tetrahydrofuran (0.63 ml) were added 4-piperidine acetic acid methyl ester (32 mg), N-ethyldiisopropylamine (65 mg) and benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP, 113 mg). The mixture was stirred at room temperature for 18 h and then concentrated to dryness. The product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>9:1) to give the title compound (82 mg) as colorless foam. MS (m/e)=583.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1I.C([O-])([O-])=O.[Na+].[Na+].[CH3:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1.C(O)C.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>[Br:1][C:2]1[C:3]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:16])[CH:22]=2)=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)c1I
Reactant: Cc1cccc(B(O)O)c1
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: CCO
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2c(F)cccc2Br)c1
Temperature: 25 °C

Procedure:
Pd(Ph3P)4 in a 500-mL round-bottom flask under N2 atmosphere was treated sequentially with a solution of 1-bromo-3-fluoro-2-iodo-benzene (30 g, 0.1 mol) in toluene (250 mL), a solution of 2N aq Na2CO3 (200 mL) and 3-methyl phenylboronic acid in ethanol (62 mL). This mixture was heated at reflux under N2 for 12 h, then cooled to rt. The mixture was partitioned between water and EtOAc. The combined organic layers were washed with brine, dried over MgSO4, evaporated and purified by column chromatography to give 6-bromo-2-fluoro-3′-methyl-biphenyl (12 g). 1H NMR (400 MHz, CD3OD): 7.03 (m, 2H), 7.48-7.04 (m, 4H), 7.50 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:48][C:49]1[N:54]=[CH:53][C:52]([C@H:55]([NH2:57])[CH3:56])=[CH:51][CH:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[CH:11]=[C:10]([C:21]([NH:57][C@@H:55]([C:52]3[CH:53]=[N:54][C:49]([CH3:48])=[CH:50][CH:51]=3)[CH3:56])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3CCCCC3=O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(C)nc3)cc(N3CCCCC3=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(2-oxopiperidin-1-yl)biphenyl-3-carboxylic acid (45 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56 mg, 0.29 mmol), 1-hydroxybenzotriazole hydrate (22 mg, 0.14 mmol), and CH2Cl2 (3 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine hydrochloride (38 mg, 0.22 mmol) and N,N-diisopropylethylamine (51 μL, 0.29 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-80% CH3CN-water [10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][CH2:6][CH3:7].[OH:8]OS([O-])=O.[K+].[OH2:14]>CO>[NH2:1][CH2:2][CH2:3][CH2:4][S:5]([CH2:6][CH3:7])(=[O:8])=[O:14]
Reactant: O=S([O-])OO
Reactant: O
Reactant: CCSCCCN
Agent: [K+]
Solvent: CO
Product: CCS(=O)(=O)CCCN
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1.0 g of 3-aminopropyl-ethyl sulfide is placed in 35 ml of methanol at 0° C.; 15.5 g of oxone in 35 ml of water are added and the mixture is stirred at 0° C. for 4 hours. 200 ml of water are added and the mixture is extracted with 3×150 ml of dichloromethane. The organic extracts are concentrated by evaporation and purified by FC (10 g of silica gel, ethyl acetate/methanol/conc. ammonia=80:15:5). The title compound is obtained: Rf (ethyl acetate/methanol/conc. ammonia=80:15:5)=0.15.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(CCN2C=C(C3SC(C(OCC)=O)=C(C)N=3)N=N2)CC1>>[CH:7]1([CH2:2][CH2:1][N:8]2[CH:12]=[C:11]([C:13]3[S:14][C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=3)[N:10]=[N:9]2)[CH2:6][CH2:5]1
Reactant: CCOC(=O)c1sc(-c2cn(Cc3ccccc3)nn2)nc1C
Agent: CCOC(=O)c1sc(-c2cn(CCC3CC3)nn2)nc1C
Product: Cc1nc(-c2cn(CCC3CC3)nn2)sc1C(=O)O
Yield: 89 %

Procedure:
Following the procedure as described in Example 3, making variations as necessary to replace ethyl 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylate with ethyl 2-(1-(2-cyclopropylethyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 89% yield: MS (ES−) m/z 277.2 (M−1).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][NH2:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:42][C:43]1[C:44]([C:61]2[CH:66]=[CH:65][C:64]([S:67][CH3:68])=[CH:63][CH:62]=2)=[CH:45][C:46](=[O:60])[N:47]([CH2:49][CH2:50][C@@:51]([CH3:59])([S:55]([CH3:58])(=[O:57])=[O:56])[C:52](O)=[O:53])[CH:48]=1>CN(C=O)C.CCOC(C)=O>[F:42][C:43]1[C:44]([C:61]2[CH:62]=[CH:63][C:64]([S:67][CH3:68])=[CH:65][CH:66]=2)=[CH:45][C:46](=[O:60])[N:47]([CH2:49][CH2:50][C@@:51]([CH3:59])([S:55]([CH3:58])(=[O:57])=[O:56])[C:52]([NH:17][O:16][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)=[O:53])[CH:48]=1
Reactant: NOC1CCCCO1
Reactant: CSc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
N,N-Diisopropylethylamine (450 uL, 2.45 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (192 mg, 1.64 mmol) and HATU (447 mg, 1.23 mmol) were added to a solution of (2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoic acid (339 mg, 0.82 mmol) in DMF (10 mL). The reaction was allowed to stir at rt for 18 h. The reaction mixture was diluted with EtOAc and washed with brine. The organics were dried (MgSO4), filtered and concentrated. The crude residue was purified via flash chromatography using a 40 g silica column and an eluent of EtOAc in n-heptane (0-100%) to afford the title compound (420 mg, 100%). MS (LCMS) m/z 511.4 (M−1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH3:19])=[CH2:18])[CH:12]=1)([CH3:10])=[CH2:9]>CC1C=CC(C)=CC=1>[CH3:18][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([CH3:10])[CH3:9])[CH:12]=1)([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[CH3:19]
Reactant: Oc1ccccc1
Reactant: C=C(C)c1cccc(C(=C)C)c1
Solvent: Cc1ccc(C)cc1
Product: CC(C)(c1ccc(O)cc1)c1cccc(C(C)(C)c2ccc(O)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 15.3 %

Procedure:
A 500-ml three-neck reactor was charged with Amberlist-15 (7.5 g, 2.6 mmols), phenol (178.5 g, 633 mmols) and p-xylene (60 ml). The contents were heated up to 80° C. in nitrogen atmosphere. Under agitation, a mixture of m-diisopropenylbenzene (m-DIPeB, 15.0 g, 31.5 mmols) and p-xylene (60 ml) was fed thereto over 3 hours at 80° C. After completion of the feed, agitation was carried out at 80° C. for 10 minutes and then Amberlist-15 was removed by filtration. The filtrate was analyzed by liquid chromatography. Bisphenol M (α, α″-bis(4-hydroxyphenyl)-1,3-diisopropylbenzene, 30.5 g, yield 93%), the intended product, and the o, p-product, the position isomer of bisphenol M (α-(4-hydroxyphenyl)-α″-(2-hydroxyphenyl)-1,3-diisopropylbenzene, 1.67 g, yield 5.1%), were obtained.
Reaction SMILES: N1CCCCC1.[CH3:7][C:8]1[N:9]=[CH:10][NH:11][C:12]=1[N+:13]([O-:15])=[O:14].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O.CN(C=O)C>CC(O)C>[N+:13]([C:12]1[NH:11][CH:10]=[N:9][C:8]=1/[CH:7]=[CH:21]/[C:17]1[S:16][CH:20]=[CH:19][CH:18]=1)([O-:15])=[O:14]
Reactant: Cc1nc[nH]c1[N+](=O)[O-]
Reactant: O=Cc1cccs1
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=[N+]([O-])c1[nH]cnc1/C=C/c1cccs1
Temperature: 100 °C
Yield: 67.8 %

Procedure:
Piperidine (1.7 g, 0.02 mol) was added to a suspension of 4-methyl-5-nitroimidazole (5 g, 0.04 mol) and 2-thiophenecarboxaldehyde (22 g, 0.2 mol) and heated at 100° C. for 15 hours. After cooling, DMF (5 mL) and IPA (15 mL) were added and the precipitate filtered from solution and washed with IPA (50 mL) to leave the product as a yellow solid (6.0 g, 69%). δH (DMSO-d6) 13.56 (1H, bs, NH), 7.90 (1H, s), 7.66 (1H, d, J=16.4), 7.66 (1H, d, J=5.0), 7.40 (1H, d, J=16.4), 7.35 (1H, d, J=3.6), 7.15 (1H, dd, J=3.6, 5.0).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#Cc1ccc2ncccc2c1
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
To a solution of quinoline-6-carboxamide (177 g, 1.03 mol) in chloroform (1.5 lit.) and triethylamine (520.15 g, 5.15 mol), trifluoroacetic anhydride (540.34 g, 2.57 mol) was added dropwise below 10° C. After 1.5 h, the pH was adjusted to 7 with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried with sodium sulphate and concentrated to afford the title compound as a brown solid (96 g, 59%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[NH2:13][N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1>C1(C)C=CC=CC=1>[N:14]1([N:13]=[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:13][N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH3:11])[N:5]=2)[CH3:2])[CH:18]=[CH:17][CH:16]=[CH:15]1
Reactant: Nn1cccc1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: Cc1ccccc1
Product: CC(=Nn1cccc1)c1cccc(C(C)=Nn2cccc2)n1
Reaction time: 48 h

Procedure:
2,6-Diacetylpyridine (345 mg, 2.11 mmol) and 1-aminopyrrole (400 mg, 4.87 mmol) were dissolved in 50 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 2 days at room temperature, the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. Yield 350 mg (57%) of diimine 11.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3](O)[CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC#N.O.CC(O)C>[CH3:16][C:15]1[C:13](=[O:14])[N:12]=[C:10]2[N:9]([C@@H:1]3[O:8][C@H:5]([CH2:6][OH:7])[C@H:3]([O:11]2)[CH2:2]3)[CH:17]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: CC#N
Solvent: O
Product: Cc1cn2c(nc1=O)O[C@@H]1C[C@H]2O[C@@H]1CO
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a dried round bottom flask containing thymidine(10.0 g, 41.6 mmol) was added triphenylphosphine (21.8 g, 82.2 mmol) and CH3CN (160 mL). The suspension was cooled to −20° C. ((40:60 iPrOH:H2O) and dry ice). To the reaction mixture was added diisopropylazodicarboxylate (16.8 g, 82.2 mmol) as CH3CN solution (60 mL) dropwise via an addition funnel, over a period of 1 hour. After the addition, the mixture was stirred for an additional 90 minutes at 20° C. The mixture was allowed to warm to 10° C. over a period of 5 hours. The reaction was then quenched with H2O (6 mL) forming a white suspension. The reaction was allowed to stand for 30 minutes and then was filtered. The collected solid was washed with cold CH3CN and dried under vacuum to afford 7.7 g (83% yield) of a white solid. If desired, the solid may be recrystallized in EtOH.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH3:23])[S:5](=[O:22])(=[O:21])[O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[CH:17]=[CH:18][C:19]#[N:20].CO.Cl>C1COCC1.O>[CH3:23][N:4]([CH3:3])[S:5](=[O:21])(=[O:22])[O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[CH2:17][CH2:18][C:19]#[N:20]
Reactant: COc1cc(C=CC#N)c(OS(=O)(=O)N(C)C)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(CCC#N)c(OS(=O)(=O)N(C)C)cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Disperse 6.7 g (0.177 mol) of sodium borohydride in 150 ml of THF. Pour in dropwise a suspension of 18.4 g (0.059 mol) of 2-(2-cyanovinyl)-4,5-dimethoxyphenyl dimethylsulphamate in 200 ml of THF. Pour in dropwise 48 ml of methanol. Heat for 3 h at 50° C. and then cool and add 1 g (0.026 mol) of sodium borohydride. Heat the reaction mixture at 50° C. for 1 h and then stir overnight at ambient temperature. Hydrolyse by pouring into the reaction mixture 60 ml of aqueous 4N HCl solution while maintaining the temperature at approximately 20° C. Add 40 g of ice and 30 ml of water and then extract twice with 200 ml of ethyl acetate each time. The organic phase is washed with water and saturated aqueous NaCl solution and then dried over MgSO4, filtered and evaporated to dryness. 17.4 g of title product are obtained.
Reaction SMILES: Br[CH:2]1C(=O)C2C(=CC=CC=2)[O:4][CH2:3]1.CN(CCCO[C:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[N:27]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:28]=1)C.Cl.C1CCN2C(=NCCC2)CC1>C(O)C>[OH:4][C:3]1[CH:2]=[CH:22][CH:23]=[CH:24][C:25]=1[C:26]1[CH:21]=[CH:20][N:28]=[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]=1
Reactant: CN(C)CCCOc1nn(Cc2ccccc2)c2ccccc12
Reactant: O=C1c2ccccc2OCC1Br
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: Oc1ccccc1-c1ccnc(-c2ccccc2)n1

Procedure:
A solution of 3-bromo-chroman-4-one (2.5 g) and benzydamine hydrochloride (1.7 g) in dry ethanol (25 ml) was refluxed for 6 hours in the presence of DBU (1.7 g). The reaction mixture was cooled, then evaporated to dryness and the residue was partitioned between ethyl acetate and a diluted hydrochloric acid aqueous solution. The organic layer was washed with a diluted sodium carbonate aqueous solution, with water, dried and evaporated to dryness to give the crude title compound. This was purified through its hydrochloride, prepared by dissolving the free base in acetone and adding an HCI ethereal solution.
Reaction SMILES: [CH2:1]=[C:2]([CH3:4])[CH3:3].[CH2:5]=O.[CH3:7][C:8]([CH3:10])=[O:9]>>[CH3:1][C:2](=[CH2:4])[CH2:3][CH2:5][CH2:7][C:8](=[O:9])[CH3:10]
Reactant: C=C(C)C
Reactant: CC(C)=O
Reactant: C=O
Product: C=C(C)CCCC(C)=O

Procedure:
Process (ii): A process in which isobutene, acetone and formaldehyde are allowed to react under conditions of a high temperature and a high pressure to give 6-methyl-6-hepten-2-one (see, e.g., German Patents No. 12 59 876 and No. 12 68 135 and U.S. Pat. No. 3,574,773).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:26]=1.Cl.[CH2:28]([N:30]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.CN.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:28][NH:30][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([N:14]2[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]3[N:26]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=3[C:15]2=[O:16])[CH:18]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)O)c1)C2=O
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1cccc(N2C[C@@H]3CCCN3c3nc(SC)ncc3C2=O)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 103.6 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic acid (364 mg, 0.982 mmol) obtained in Step 1 of Example 56 was dissolved in DMF (10 mL), and the mixture was stirred at room temperature for 3.5 hours after adding 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (207 mg, 1.08 mmol), 1-hydroxybenzotriazole.monohydrate (166 mg, 1.08 mmol), methylamine hydrochloride (100 mg, 1.47 mmol), and triethylamine (0.204 mL, 1.47 mmol). The mixture was diluted by addition of ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)—N-methyl-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamide (390 mg, 91%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:37][NH:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(N(CC)CC)C>[ClH:31].[CH2:39]([N:38]([CH3:37])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@@H:20]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[C:19]4[CH:33]=[CH:34][CH:35]=[CH:36][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCNC
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C3)cc1
Solvent: CCN(CC)CC
Product: CCCCN(C)CCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C3)cc1
Product: Cl

Procedure:
This was synthesized by using (S)-4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-methylbutan-1-amine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=135-145° C. 1H NMR 400 MHz (DMSO-d6) δ 10.52 (s, 2 H), 9.70 (s, 1 H), 8.33-8.28 (m, 2 H), 7.78-7.76 (m, 2 H), 7.51-7.42 (m, 4 H), 7.24-7.22 (d, 2 H), 7.11-7.09 (m, 1 H), 7.02-7.00 (m, 1 H), 4.46 (t, J=6.4 Hz, 1 H), 3.28-3.11 (m, 5 H), 3.00-2.96 (m, 3 H), 2.75 (d, 3 H), 1.67-1.61 (m, 2 H), 1.33-1.27 (m, 2 H), 0.89 (t, J=7.6 Hz, 3 H). LCMS m/e 531 (M+H).