Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]([CH3:16])([SH:15])[CH3:14].[H-].[Na+].[CH3:21]I>O1CCCC1>[CH3:21][S:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][C:13]([SH:15])([CH3:16])[CH3:14]
Reactant: CC(C)(S)CNc1ccccc1NCC(C)(C)S
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC(C)(C)CNc1ccccc1NCC(C)(C)S
Reaction time: 1 h
Yield: 79.1 %

Procedure:
1,2-Bis (2-Mercapto-2-methylpropylamino)benzene (0.47 g, 1.69×10-3 mol), and 0.09 g (1.85×10-3 mol, 110 M %) sodium hydride were dissolved in 25 ml tetrahydrofuran. Methyl iodide (0.080 ml, 1.27×10-3 mol, 75 M %) was added, and the mixture was stirred under nitrogen for 1 hour. The excess hydride was destroyed by the slow addition of 10 ml 0.5 M HCl. The mixture was shaken with a mixture of 100 ml ether and 100 ml 0.5 N HCl. The aqueous layer was extracted with an additional 50 ml portion of ether, and the combined ether layers were washed with 100 ml saturated NaCl. The ether layer was then dried over anhydrous Na2SO4. Rotary evaporation yielded 0.30 g (94% yield) of 1-[2-methylthio-2-methylpropylamino]-2-(2-mercapto-2-methylpropylamino)benzene as a yellow oil. Isolation was performed by radial chromatograph on a 1 mm silica plate, using petroleum ether: ethyl acetate-80:20 as the eluting solvent to give yielding a mixture of the 1-[2-methylthio-2-methylpropyl- amino]-2-(2-mercapto-2-methylpropylamino)benzene, S,S'-dimethyl, and the dithiol starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]3[C:15]([NH2:16])=[N:14][NH:13][C:9]3=[N:10]2)=[CH:5][CH:4]=1.I[CH:18]([CH3:20])[CH3:19].[H-].[Na+]>>[CH:18]([N:13]1[C:9]2=[N:10][C:11]3[C:6]([CH:7]=[C:8]2[C:15]([NH2:16])=[N:14]1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)([CH3:20])[CH3:19]
Reactant: COc1ccc2cc3c(N)n[nH]c3nc2c1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2cc3c(N)nn(C(C)C)c3nc2c1

Procedure:
The intermediate 1-isopropyl-7-methoxy-1H-pyrazolo[3,4-b]quinolin-3-amine was prepared by alkylation of 7-methoxy-1H-pyrazolo[3,4-b]quinolin-3-amine (Example 3d) with 2-iodopropane in the presence of sodium hydride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:23][CH3:24])[C:14]([NH:16][C:17]([C:21]#[N:22])([CH3:20])[CH2:18][OH:19])=[O:15])=[CH:7][CH:6]=2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:23][CH3:24])[C:14]([NH:16][C:17]([C:21]#[N:22])([CH3:20])[CH:18]=[O:19])=[O:15])=[CH:7][CH:6]=2
Reactant: CSC(Oc1ccc2ncc(Br)cc2c1)C(=O)NC(C)(C#N)CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CSC(Oc1ccc2ncc(Br)cc2c1)C(=O)NC(C)(C#N)C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
2-(3-Bromo-quinolin-6-yloxy)-N-(1-cyano-2-hydroxy-1-methyl-ethyl)-2-methylsulfanyl acetamide (0.660 g) from Stage 1 above in dichloromethane (25 ml) was treated with Dess-Martin periodinane (0.819 g). The reaction mixture was stirred at R.T. for 2 h 30. The reaction mixture was quenched with sat. aqueous NaHCO3 and sat. aqueous sodium thiosulphate. The reaction mixture was vigorously stirred at rt. for 30 minutes after which time the two phases were separated. The organic layer was washed with sat. aqueous. NaHCO3. After separation the organic phase was dried over sodium sulphate, filtered and evaporated to yield 0.397 g of 2-(3-Bromo-quinolin-6-yloxy)-N-(1-cyano-1-methyl-2-oxo-ethyl)-2-methylsulfanyl-acetamide as a crude product which was used in the next step without any further purification.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2]1.CN(C)C=O.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:1][CH2:2][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5][C:6]1=2)[CH3:35]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (3.557 g, 12.42 mmol) and N,N-dimethylformamide (30 mL) was added 60% sodium hydride (0.596 g, 14.90 mmol). The mixture stirred for 1 h, and then cooled in a 0° C. bath. Ethyl bromoacetate was added, and the mixture warmed to room temperature. Water then was added and the mixture was evaporated in vacuo. The residue was taken up in ethyl acetate and washed with water. Evaporation and trituration with hexanes provided 3.289 g of the title compound, the structure of which is shown in FIG. 6 as (23) (where n=1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:12][NH:13][CH3:14].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:13]([CH3:14])[CH3:12]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(F)c(CN(C)C)c1
Yield: 97 %

Procedure:
2-Fluoro-5-methoxybenzaldehyde (2.62 g, 17.0 mmol), dimethylamine (2M in methanol, 17 mL, 34 mmol) and sodium cyanoborohydride (1.17 g, 18.7 mmol) were stirred at ambient temperature in a solution of glacial acetic acid (2 mL) in methanol (100 mL) for 66 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to give (2-fluoro-5-methoxybenzyl)dimethylamine (3.02 g, 97%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[CH3:27][O:28][C:29]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[CH:40][C:30]=1[C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)=[O:32]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:42]2[CH:41]=[CH:40][C:30]([C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[O:32])=[C:29]([O:28][CH3:27])[CH:43]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(=O)Nc1ccccn1
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Product: COc1cc(-c2nc([C@@H]3CCCN3)n3ccnc(N)c23)ccc1C(=O)Nc1ccccn1
Yield: 56.6 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and 2-methoxy-N-(pyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (intermediate 18) to afford the title compound (175 mg, 56.6%).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CO.[BH4-].[K+]>[OH:13][CH:12]1[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:18])[N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1c2ccccc2C(O)N1Cc1ccccc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 92.4 %

Procedure:
3-Hydroxy-2-benzyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 10.2 g of N-benzylphthalimide in 100 cm3 of methanol and 2.6 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and 50 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C., followed by addition of a further 50 cm3 of distilled water. The aqueous phase is extracted 3 times with 50 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 9.5 g of 3-hydroxy-2-benzyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white powder. (Rf=0.20, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])[CH:3]=1
Reactant: CC(N)c1cc(Br)ccn1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(C)c1cc(Br)ccn1

Procedure:
To a solution of 1-(4-bromopyridin-2-yl)ethanamine (2.3 g, 11.44 mmol) in chloroform (30 mL) was added acetic anhydride (2.16 mL, 22.88 mmol) dropwise at 0° C. The reaction was then quenched with ice water (40 mL) and extracted with chloroform (2×50 mL). The organic extracts were combined, then washed with 1M NaOH (50 mL), dried over Na2SO4, concentrated, and purified by column chromatography (gradient 0 to 5% MeOH/DCM) to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=5.3 Hz, 1H), 7.42 (s, 1H), 7.36 (dd, J=5.3, 1.7 Hz, 1H), 6.71 (br s, 1H), 5.10 (p, J=7.0 Hz, 1H), 2.02 (s, 3H), 1.45 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH:1]1([N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[C:31]([Cl:56])=[C:32]([N:38]2[CH2:43][CH2:42][C@@H:41]([O:44][Si](C(C)(C)C)(C)C)[C@H:40]([NH:52][C:53](=[O:55])[CH3:54])[CH2:39]2)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=1>>[Cl:56][C:31]1[C:30]([NH:29][C:7]2[N:6]=[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=2)=[CH:35][C:34]([C:36]#[N:37])=[CH:33][C:32]=1[N:38]1[CH2:43][CH2:42][C@@H:41]([OH:44])[C@H:40]([NH:52][C:53](=[O:55])[CH3:54])[CH2:39]1
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(=O)N[C@@H]1CN(c2cc(C#N)cc(N)c2Cl)CC[C@H]1O[Si](C)(C)C(C)(C)C
Product: CC(=O)N[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1O

Procedure:
(+/−)-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl amino) imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-hydroxypiperidin-3-yl)acetamide was prepared starting from 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 2) and (+/−)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-4-((tert-butyldimethylsilyl)oxy) piperidin-3-yl)acetamide using a method analogous to that used to prepare Example 171.
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.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH:55]([C:58]1[O:62][N:61]=[C:60]([C:63](O)=[O:64])[CH:59]=1)([CH3:57])[CH3:56]>>[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:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:63]([C:60]2[CH:59]=[C:58]([CH:55]([CH3:57])[CH3:56])[O:62][N:61]=2)=[O:64])[CH2:49][CH2:48]1
Reactant: CC(C)c1cc(C(=O)O)no1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 18 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using 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]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-isopropylisoxazole-3-carboxylic acid as starting materials in 18% yield. LCMS for C31H34ClN8O3 (M+H)+: m/z=601.2.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:22]([O:24]C)=O)[C:15](=[CH:20][CH:21]=1)[C:16]([O:18]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:28](OCC)(=O)C>CC(C)=O>[O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:20][CH:21]=1)[C:16](=[O:18])[CH2:28][C:22]2=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCCCOc2ccccc2)cc1C(=O)OC
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CC(=O)c2cc(OCCCOc3ccccc3)ccc21
Yield: 22 %

Procedure:
A solution of dimethyl 4-(3-phenoxypropoxy)phthalate (13.6g, 0.0395 mole) in ethyl acetate (12 ml) was added to a 50% dispersion of sodium hydride in mineral oil (2.54 g) and the mixture heated at reflux for 4 hrs. After cooling, the mixture was triturated with 50% ethanol, ether and the yellow solid filtered off and added to a hot (70°-80° C.) 10% solution of hydrochloric acid (150 ml). After 2 mins a yellow oily solid separated which was isolated by decantation and taken up in acetone from which it crystallised on concentration to give 2.533g (22%) of material of m.p. 91°-94° C., νmax (mull) 1740, 1710, 1605 cm-1 ; τ(DMSO) 7.78 (2H quintet; J 6.4Hz); 6.68 (2H, s); 5.83 (2H, t, J 6.4Hz); 5.62 (2H, t, J 6.4Hz); 3.21-2.44 (7H, m); 2.12 (1H, m). (Found; C, 72.97; H, 5.61; C18H16O4 requires; C, 72.96; H, 5.44%).
Reaction SMILES: [CH2:1]([C:5]1[S:21][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]([NH2:20])=O)=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[S:21][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]#[N:20])=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Yield: 55.7 %

Procedure:
From 4.0 g (0.0133 mol) of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide (Example 24), 100 ml of phosphorus oxychloride and 100 ml of chloroform and refluxing on a steam bath for four hours, following the procedure of Example 27, there is obtained 2.1 g of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 216°-217° C. after recrystallization from pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([S:13][C:14]1[S:15][C:16]2[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=2[N:18]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[CH3:2].S(OCC)(O[CH2:29][CH3:30])(=O)=O>[OH-].[Na+]>[CH2:1]([O:3][C:4](=[O:24])[C:5]([S:13][C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][CH2:29][CH3:30])[CH:20]=[CH:19][C:17]=2[N:18]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCOC(=O)C(C)(Sc1nc2ccc(O)cc2s1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C(C)(Sc1nc2ccc(OCC)cc2s1)c1ccccc1

Procedure:
3.59 g. of 2-(6-hydroxybenzothiazol-2-ylthio)-2-phenylpropionic acid ethyl ester is dissolved in 15 ml of 1 N sodium hydroxide solution and 1.6 g of diethyl sulfate is added dropwise, while stirring. After stirring for a total of 1 hour, the mixture is worked up in the customary manner to give 2-(6-ethoxybenzothiazol-2-ylthio)-2-phenylpropionic acid ethyl ester, m.p. 92°-94°.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH3:26])[C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=3[C@@H:9]3[C@H:14]([NH:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH3:26])[C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=3[C@@H:9]3[C@H:14]([NH:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CN[C@@H]1CCCN2c3cc(Cl)ccc3N(C)c3ccccc3[C@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN1c2ccccc2[C@@H]2[C@H](NCC(=O)O)CCCN2c2cc(Cl)ccc21
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
To a solution of ethyl trans-[(7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)amino]acetate (35 mg, 0.09 mmol) in dioxane (1 mL) was added 4N (aq) NaOH (250 ul). The reaction mixture was stirred at 65° C. for 1.5 h. It was diluted with water (25 mL) whereafter the pH was adjusted to pH 2 with 2N (aq) HCL. The mixture was extracted with ethyl acetate (2×), washed with water and brine, dried (MgSO4) and evaporated. The crude product was purified with LC-MS to afford the title compound (4 mg, 12%). Data (m/z)=372 (M+H)+.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:36][CH2:37][OH:38]>CN(C)C=O>[CH:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:36][CH2:37][OH:38])=[CH:26][CH:27]=2)=[CH:9][CH:10]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(O)cc3)nc3ccccc3c2=O)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(-n2c(-c3ccc(OCCO)cc3)nc3ccccc3c2=O)cc1

Procedure:
To a solution of 2-amino-N-(4-sec-butylphenyl)-benzamide (0.500 g, 1.86 mmol) in N,N-dimethylformamide (9 mL) under nitrogen atmosphere was added 4-hydroxy-benzaldehyde (0.450 g, 3.73 mmol) followed by iodine (0.560 g, 2.23 mmol) and potassium hydroxide (0.120 g, 2.23 mmol). The resulting mixture was heated at 110° C. overnight, then the solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, washed with water and dried over sodium sulfate. The crude oil (0.97 g) was purified by column chromatography (silica gel 230-400 mesh; 1/1 hexanes/EtOAc as eluent) to give pure 3-(4-sec-butylphenyl)-2-(4-hydroxyphenyl)-3H-quinazolin-4-one as a yellow solid. Yield: 0.33 g (47.8%). To a mixture of 3-(4-sec-butylphenyl)-2-(4-hydroxyphenyl)-3H-quinazolin-4-one (0.11 g, 0.31 mmol) and potassium carbonate (0.13 g, 0.93 mmol) in N,N-dimethylformamide (3.5 mL) under nitrogen atmosphere was added 2-chloroethanol (0.032 mL, 46 mmol). The reaction mixture was heated at reflux for 14 hours, then the solvent was removed under reduced pressure and the residue was diluted with ethyl acetate, washed with 5% aqueous solution of sodium hydroxide, brine, and dried over sodium sulfate. The crude solid (0.13 g) was purified by column chromatography (silica gel 230-400 mesh; 10/0 to 1/1 hexanes/EtOAc, then 10/0 to 9.4/0.6 methylene chloride/MeOH as eluent) and triturated with Et2O to give the pure title compound as a light brown solid. Yield: 60 mg, (46.3%). MP 172.8-174.9° C. 1H-NMR (400 MHz, CDCl3): δ 8.35 (d, 1H), 7.80 (d, 2H), 7.50 (m, 1H), 7.28 (d, 2H), 7.14 (d, 2H), 7.05 (d, 2H), 6.72 (d, 2H), 4.00 (m, 2H), 3.95 (m, 2H), 2.58 (m, 1H), 1.95 (s, OH), 1.65-1.48 (m, 2H), 1.20 (d, 3H), 0.75 (t, 3H). MS (ES+) m/z: 415.09 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([O:11][CH3:12])[CH:3]=1.ClC1C=C(Cl)C=CC=1C1[C:26]([C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)=[CH:25][N:24]=[C:23]([NH:32][CH2:33][CH2:34][NH:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][N:37]=2)[N:22]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[C:26]([C:27]3[NH:31][CH:30]=[CH:29][N:28]=3)=[CH:25][N:24]=[C:23]([NH:32][CH2:33][CH2:34][NH:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][N:37]=3)[N:22]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Product: COc1cc(Cl)ccc1-c1nc(NCCNc2ccc([N+](=O)[O-])cn2)ncc1-c1ncc[nH]1

Procedure:
[4-(4-chloro-2-methoxyphenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 4-chloro-2-methoxybenzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[NH:7][N:6]=[N:5][C:4]=1[C:8]([O:10]CC)=[O:9].[OH-].[Na+].Cl>>[F:14][C:2]([F:1])([F:13])[C:3]1[NH:7][N:6]=[N:5][C:4]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1nn[nH]c1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nn[nH]c1C(F)(F)F
Yield: 83.7 %

Procedure:
Ethyl 5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxylate (0.312 g) was stirred in aqueous N sodium hydroxide (3.8 mL) and heated under reflux for 90 min. The cooled solution was acidified with aqueous hydrochloric acid and extracted with ethyl acetate. The extracts were washed with brine then dried and evaporated to leave a colourless solid (0.226 g).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11](=O)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[N:5]1)([CH3:3])[CH3:2].[NH2:21][C:22](=[C:25]([NH2:28])[C:26]#[N:27])[C:23]#[N:24]>C(#N)C>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:21]=[C:22]([C:23]#[N:24])[C:25]([C:26]#[N:27])=[N:28][C:12]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1nc(C(=O)C(=O)c2ccccc2)ccc1=O
Reactant: N#CC(N)=C(N)C#N
Solvent: CC#N
Product: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2)ccc1=O
Temperature: 72.5 °C
Yield: 89.2 %

Procedure:
A mixture of 1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-phenyl-1,2-ethanedione (1.15 g) and 2,3-diamino-2-butenedinitrile (0.46 g) in acetonitrile (6 ml) was heated at 70-75° C. for 3 hours. A reaction mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2,3-pyrazinedicarbonitrile as a solid (1.30 g).
Reaction SMILES: Cl[C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:24][CH2:25][CH2:26][F:27])[N:3]=1.[CH3:28][NH2:29]>C1COCC1>[F:27][CH2:26][CH2:25][O:24][C:4]1[N:3]=[C:2]([NH:29][CH3:28])[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]=1[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]1)=[O:7]
Reactant: CN
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(Cl)nc1OCCF
Solvent: C1CCOC1
Product: CNc1nc(OCCF)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared from 6-chloro-2-(2-fluoro-ethoxy)-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (1.00 g, 2.30 mmol) and methylamine (2 M in THF; 2.75 mL, 5.50 mmol) in THF (15 mL) in analogy with method described in example 1d.
Reaction SMILES: CON(C)[C:4](=[O:17])[C@H:5]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)[CH2:6][CH:7]=[CH2:8].[CH3:19][Li]>O1CCCC1>[Cl:16][C:11]1[CH:10]=[C:9]([C@H:5]([CH2:6][CH:7]=[CH2:8])[C:4](=[O:17])[CH3:19])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: C=CC[C@H](C(=O)N(C)OC)c1ccc(Cl)c(Cl)c1
Reactant: [Li]C
Solvent: C1CCOC1
Product: C=CC[C@H](C(C)=O)c1ccc(Cl)c(Cl)c1
Reaction time: 3 h
Yield: 92.9 %

Procedure:
A solution of 319 mg (1.11 mmoL) of N-methoxy-N-methyl-2-(S)-(3,4-dichlorophenyl)-4-pentenamide (from Step 1 above) in 10 mL of dry tetrahydrofuran was cooled to -70° C. and treated with 1.0 mL (1.40 mmol) of methyllithium and stirred between -70° C. to -40° C. After 3 hours, the reaction was quenched with 5 mL of water, and diluted with 10 mL of ethyl acetate. The layers were separated and the organic layer was washed with water (3×10 mL). The aqueous layers were extracted with 10 mL of ethyl acetate. The combined organic layers were washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on 44 g of silica gel using 1:3 v/v ethyl acetate/hexane as the eluant afforded 250 mg (93%) of the title compound as a clear oil.