Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1.[Cl:22][C:23]1[C:36]([CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:35]([Cl:43])[CH:34]=[CH:33][C:24]=1[O:25][C@H:26]1[CH2:29][C@H:28]([CH2:30][NH:31][CH3:32])[CH2:27]1>C1COCC1>[ClH:22].[Cl:22][C:23]1[C:36]([CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:35]([Cl:43])[CH:34]=[CH:33][C:24]=1[O:25][C@H:26]1[CH2:29][C@H:28]([CH2:30][N:31]([CH3:32])[C:19]([CH:16]2[CH2:15][CH2:14][O:13][CH2:18][CH2:17]2)=[O:21])[CH2:27]1
Reactant: CNC[C@H]1C[C@H](Oc2ccc(Cl)c(CN3CCCC3)c2Cl)C1
Reactant: O=C(O)C1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C[C@H]1C[C@H](Oc2ccc(Cl)c(CN3CCCC3)c2Cl)C1)C(=O)C1CCOCC1
Product: Cl
Reaction time: 0.5 h

Procedure:
CDI (227 mg, 1.40 mmol) was added to a solution of tetrahydropyran-4-yl-carboxylic acid (CAS 5337-03-1, 182 mg, 1.40 mmol) in THF (3 mL). The mixture was stirred for 30 min, and a solution of Example 377, ({trans-3-[2,4-Dichloro-3-(pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl)methylamine (400 mg, 1.165 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 16 h at room temperature and evaporated. CHCl3 (5 mL), a saturated solution of K2CO3 (0.5 mL), and water (0.5 mL) were added to the residue under stirring. The layers were separated, and the aqueous one was subjected to extraction with chloroform. The combined extracts were dried and evaporated. The residue was purified by chromatography (silica gel, 63-100 μm, 10 g, CHCl3/MeOH 100:0→80:10). Fractions containing the target product were evaporated. The residue was dissolved in ether (1 mL), and 4M HCl/dioxane (0.3 mL) was added under stirring. The obtained mixture was evaporated and dryed in vacuo to afford the title compound (490 mg, 85%) as a light-yellow amorphous solid. LCMS data: 455.1, 456.1, 457.1 (M+H) (calculated for C23H32Cl2N2O3 455.43). 1H NMR-data (DMSO-d6): 10.09 (brs, 1H, NH+), 7.55, 7.57 (2d, 1H, J=9 Hz, Ar—H); 7.12, 7.09 (2d, 1H, J=9 Hz, Ar—H); 4.88-5.09 (m, 1H); 4.60, 4.61 (2s, 2H, CH2); 3.74-3.90 (m, 2H), 3.23-3.58 (m, 8H); 2.80, 3.03 (2s, 3H, NCH3), 2.81-2.92 (m, 1H), 2.54-2.69 (m, 1H), 1.85-2.35 (m, 8H); 1.45-1.69 (m, 4H).
Reaction SMILES: [CH2:1]([C:8]1([O:13][C:14]([NH:16][C@@H:17]([CH2:22][CH2:23][CH2:24][CH3:25])[C:18](OC)=[O:19])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].[C:29]1([P:35](=[CH:48][C:49]#[N:50])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>O1CCCC1.O.CN(C)C1C=CN=CC=1>[C:49]([C:48](=[P:35]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:18]([C@@H:17]([NH:16][C:14](=[O:15])[O:13][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:22][CH2:23][CH2:24][CH3:25])=[O:19])#[N:50]
Reactant: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCC1)C(=O)OC
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](NC(=O)OC1(Cc2ccccc2)CCCC1)C(=O)C(C#N)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To 1.31 g (3.77 mmol) of methyl(2S)-2-({[(1-benzylcyclopentyl)oxy]carbonyl}amino)hexanoate in 12 mL of tetrahydrofuran:water (1:1) was added 221.5 mg (5.28 mmol) of lithium hydroxide monohydrate and the mixture was stirred at room temperature for 4 h. The solution was concentrated and extracted with ethyl acetate. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 19 mL of dichloromethane, then 23.0 mg (188.5 μmol) of 4-dimethylaminopyridine was added. To this solution was added 1.19 g (3.96 mmol) of (triphenylphosphoranylidene)acetonitrile, followed by 799.2 mg (4.15 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide, and the mixture was stirred at room temperature for 19 h. Water was added to the solution and it was extracted with ethyl acetate. The organic layer was washed with 10% citric acid, followed by saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:1) to give 789.8 mg (34%) of 1-benzylcyclopentyl(1S)-1-[cyano(triphenylphosphoranylidene)acetyl]pentylcarbamate. Rf=0.31 (1:1 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.76-7.66 (m, 3H), 7.64-7.54 (m, 12H), 7.20-7.14 (m, 5H), 6.90 (d, J=8 Hz, 1H), 4.58-4.50 (m, 1H), 3.24 (ABq, JAB=14 Hz, ΔνAB=31 Hz, 2H), 1.88-1.66 (m, 4H), 1.64-1.44 (m, 6H),1.42-1.14 (m, 4H), 0.89 (t, J=7 Hz, 3H); ES-LCMS m/z 617 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[OH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([O-:34])=[O:33])=[CH:26][C:25]=1[O:35][CH3:36].N1C=CC=C[CH:38]=1.CO>C1(C)C=CC=CC=1.CN(C=O)C.CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([O:34][CH3:38])=[O:33])=[CH:26][C:25]=1[O:35][CH3:36])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: c1ccncc1
Reactant: COc1cc(/C=C/C(=O)[O-])ccc1OCCCCCCO
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(OCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c(OC)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 63.8 %

Procedure:
17.9 g (78 mmol) of 3,5-dinitrobenzoyl chloride are dissolved in 147 mL of toluene and 20 drops of DMF were incorporated. 24 g (78 mmol) of (2E)-3-{4-[(6-hydroxyhexyl)oxy]-3-methoxyphenyl}prop-2-enoate, 0.475 g (4 mmol) of 4-dimethylaminopyridine and 9.23 g (117 mmol) of pyridine are added. The mixture is stirred at room temperature for 96 hours. The solution is then heated up to 60° C. and 58 ml of MeOH are added. The suspension is stirred at room temperature for 1 hour and at 0° C. for 1 hour. The precipitate is filtered off. Chromatography of the residue using toluene: ethyl acetate 19:1 following by toluene: ethyl acetate 9:1 yielded 25 g (64%) of pure 6-{2-methoxy-4-[(1E)-3-methoxy-3-oxoprop-1-enyl]phenoxy}hexyl 3,5-dinitrobenzoate as an orange powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:33][C:32]([C:34](O)([CH3:36])[CH3:35])=[CH:31][CH:30]=1)[CH:7]=[CH:6]2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:34]([C:32]1[S:33][C:29]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[O:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:18][CH:19]=2)=[CH:30][CH:31]=1)([CH3:36])[CH3:35]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C(C)(C)O)s3)ccc2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C(C)C)s3)ccc2c1
Yield: 93.7 %

Procedure:
Add 2-(5-(6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-yl)thiophen-2-yl)propan-2-ol (84 mg; 0.16 mmol), triethylsilane (1.7 mL) and dichloromethane (0.85 mL) to a flask under argon. Add trifluoroacetic acid (0.81 mL) and stir the resulting mixture for 45 minutes. Load the mixture onto an SCX acidic ion exchange column. Flush the column with 1:2 methanol/dichloromethane and elute with 1:2 2M ammonia in methanol/dichloromethane. Concentrate the ammonia containing eluent in vacuo to give the title compound (73.1 mg; 0.15 mmol): Mass spectrum (m/z): 502 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:7]=12.[CH3:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>>[ClH:1].[CH3:16][O:15][CH2:14][CH2:13][N:8]1[C:7]2=[C:2]([NH:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([CH3:17])=[CH:19][CH:20]=3)[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]1[CH3:12]
Reactant: COCCn1c(C)c(C)c2ccnc(Cl)c21
Reactant: Cc1ccc(CN)cc1
Product: COCCn1c(C)c(C)c2ccnc(NCc3ccc(C)cc3)c21
Product: Cl
Yield: 47 %

Procedure:
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-1-(2-methoxyethyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 47%)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:27]=3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Product: CS(=O)(=O)c1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1

Procedure:
5-Chloro-2-iodo-7-morpholinothiazolo[5,4-d]pyrimidine was reacted with 3-(methylsulfonyl)phenylboronic acid via General Procedure A to give crude 5-chloro-2-(3-(methylsulfonyl)phenyl)-7-morpholinothiazolo[5,4-d]pyrimidine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 132 after purification by reverse HPLC. MS (Q1) 470 (M+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:11][Mg]Cl.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([C:8]([NH:9][C:14](=[O:16])[CH3:15])=[CH2:11])=[N:6][CH:7]=1
Reactant: C[Mg]Cl
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ncc(Br)cc1F
Solvent: Cc1ccccc1
Product: C=C(NC(C)=O)c1ncc(Br)cc1F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Compound of Step 3 (1 eq) was dissolved in toluene (10 vol). The batch was cooled to −10° C. and MeMgCl (1.5 eq) was added maintaining the temperature<0° C. The mixture was aged for 1 h and acetic anhydride was added over approximately 30 min maintaining the temperature<0° C. The reaction was aged for 18 h at −10° C. The mixture was quenched with half-saturated NaHCO3 (6 vol) and aged at 20-25° C. for 30 min. The layers were separated and the organic layer was washed with water (5 vol), 10% aqueous Na2SO4 (2×5 vol) and water (2×5 vol). The batch was concentrated under vacuum to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14](N(C)C)=[O:15])[CH2:10]1.[C:19]1(C)C=CC=CC=1.C[Mg]Br.Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14](=[O:15])[CH3:19])[CH2:10]1
Reactant: Cc1ccccc1
Reactant: CN(C)C(=O)C1=NOC(c2c(F)cccc2F)C1
Agent: C[Mg]Br
Agent: Cl
Solvent: O
Product: CC(=O)C1=NOC(c2c(F)cccc2F)C1
Temperature: -5 °C

Procedure:
To a 1000-mL flask equipped with thermometer and addition funnel were added 5-(2,6-difluorophenyl)-4,5-dihydro-N,N-dimethyl-3-isoxazolecarboxamide (i.e. the product of Step A) (80.0 g, 0.31 mol) and toluene (320 mL). The reaction mixture was cooled to −5° C., and a solution of methyl magnesium bromide (3.0 M in tetrahydrofuran, 120 mL, 0.36 mmol) was added dropwise while maintaining the temperature between −10 to −5° C. When gas chromatography analysis of the reaction mixture showed about 2% of 5-(2,6-difluorophenyl)-4,5-dihydro-N,N-dimethyl-3-isoxazolecarboxamide remaining, the reaction mixture was poured into a stirred solution of concentrated hydrochloric acid (80 mL) and water (320 mL) while maintaining the temperature between 10 to 30° C. The organic layer was separated, washed with saturated aqueous sodium chloride solution (80 mL), and then concentrated under reduced pressure. The resulting oil was crystallized from hexanes (100 mL), collected by filtration, washed with hexanes, and dried in a vacuum oven overnight at 23° C. to provide the title compound as a waxy, off-white solid (65 g), melting at 47-50° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:14]([C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=[N:18][C:17]=1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH3:15].C(=O)([O-])[O-:37].[Cs+].[Cs+].CS(C)=O>O>[CH2:14]([C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=[N:18][C:17]=1[NH:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([NH2:13])=[O:37])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:33][CH:34]=1)[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(-c2ccccc2)nnc1Nc1ccc(O)cc1
Reactant: N#Cc1ccc2c(Cl)ccnc2c1
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc(-c2ccccc2)nnc1Nc1ccc(Oc2ccnc3cc(C(N)=O)ccc23)cc1

Procedure:
A microwave reaction vial was charged with 4-chloroquinoline-7-carbonitrile (97.1 mg, 0.515 mmol), 4-(4-ethyl-6-phenylpyridazin-3-ylamino)phenol (150 mg, 0.515 mmol), cesium carbonate (252 mg, 0.772 mmol) and 2.6 mL of DMSO. The vial was sealed, and the reaction mixture was irradiated in the microwave at 150° C. for 15 min. Upon cooling the mixture was poured into water and the resulting solids were filtered and washed with water. The crude solids were dissolved in 90/10/1 CH2Cl2/MeOH/NH4OH and purified by silica gel chromatography, 5-100% 90/10/1: CH2Cl2 over 25 min which provided 4-(4-(4-ethyl-6-phenylpyridazin-3-ylamino)phenoxy)quinoline-7-carboxamide as a tan solid. MS m/z=462 [M+H]+. Calc'd for C28H23N3O2: 461.52.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[NH:4][C:3]2=[O:20])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC2N=C(c3ccccc3F)c3ccccc3NC2=O)cc1
Reaction time: 8 h
Yield: 109.8 %

Procedure:
1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (116 mg, 0.43 mmole) and p-toluenesulfonyl chloride (82 mg, 0.43 mmole) were combined at room temperature in 5 ml of methylene chloride. The pH of the reaction mixture was then adjusted to 8.5 with triethylamine and stirring was continued at room temperature overnight. The reaction mixture was partitioned between methylene chloride and 10% citric acid solution. The phases were separated and the organic layer was washed in succession with 10% citric acid solution (1×30 ml), saturated sodium bicarbonate solution (2×30 ml) and brine. The dried (MgSO4) extracts were concentrated to yield 200 mg of crude product. Recrystallization from ethyl acetate afforded the analytical sample as white needles, m.p. 215°-216° C.
Reaction SMILES: [S].Br[Mg][CH:4]1[CH2:6][CH2:5]1.C1COCC1.[S:12](=O)(=O)(O)O.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:4]1([S:12][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[CH2:6][CH2:5]1
Reactant: O=S(=O)(O)O
Reactant: Br[Mg]C1CC1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [S]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CSC2CC2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sulfur (0.91 g; 27.5 mmol) was added portions wise to a stirred 0.5M solution of bromo-(cyclopropyl)magnesium in THF (50.0 ml; 25.0 mmol). The batch was stirred at 50° C. for 1 hour and then cooled to 0° C. Lithium tetrahydridoaluminate(1-) (522 mg; 13.8 mmol) was cautiously added under stirring. The batch was stirred for 30 minutes at 50° C. and cooled to 0° C. again. Water (2 ml) was cautiously added under stirring. Finally, sulfuric acid (5%; 100 ml) was cautiously added and the batch was stirred for 10 minutes. The organic phase was separated and the aqueous phase was extracted with diethyl ether (2×). The combined organic phases were washed with saturated aqueous ammonium chloride solution (2×), aqueous sodium bicarbonate solution (5%, 2×), water (2×) and saturated aqueous sodium chloride solution (2×). The organic phase was dried (magnesium sulfate) and filtered before it was slowly added to a stirred batch of 1-(chloromethyl)-3-nitrobenzene (2.15 g; 12.5 mmol) and potassium carbonate (2.59 g; 18.8 mmol) in DMF (40 ml). The batch was stirred at 85° C. overnight. After cooling, the batch was filtered over celite and concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water (2×) and saturated aqueous sodium chloride solution (2×). The organic phase was dried (sodium sulfate), filtered and concentrated. The residue was purified by chromatography (hexane/ethyl acetate 8:2) to give the desired product (2.38 g; 11.4 mmol).
Reaction SMILES: CCCCCC.[O-:7][CH2:8][CH3:9].[Na+].Cl[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1>C(O)C>[CH2:8]([O:7][C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH3:9]
Reactant: Clc1nc2ccccc2s1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Product: CCOc1nc2ccccc2s1
Temperature: 25 °C

Procedure:
Exactly 5.8 g of hexane-wet sodium spheres (0.02 mole) was carefully dissolved in 100 ml of anhydrous ethanol. To the resulting cooled sodium ethoxide solution, stirring at 25° C. under nitrogen, was added a solution of 33.8 g (0.2 mole) of 2-chlorobenzothiazole in 100 ml of ethanol over a seven minute interval. There was a strong exotherm during this addition. The reaction mixture was heated to a reflux over 15 min and held at reflux for one hour. The apparatus was then fitted for downward distillation and the ethanol distilled from the reaction mixture at atmospheric pressure over a period of one hour. The cooled oily residue was dissolved in 50 ml of methylene chloride and rapidly stirred for 10 min with 400 ml of water. The organic layer was separated, dried over anhydrous potassium carbonate and stripped of solvent under vacuum. The crude product was distilled under reduced pressure to give 33.15 g (93%) of analytically pure 2-ethoxybenzothiazole, b.p. 78°-80° C., 0.11mm. (lit b.p. 80°-81°, 0.2 mm.) : UV (MeOH):λmax 218 nm (ε=31,100),λmax 245 nm (ε=7,800),λmax 277 nm (ε=1,100),λmax 287 nm (ε=1,060).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:22]>CO>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:22])[C:11]=2[N:12]=[CH:13]1
Reactant: N
Reactant: Clc1nc2ccccc2c2c1ncn2Cc1ccccn1
Solvent: CO
Product: Nc1nc2ccccc2c2c1ncn2Cc1ccccn1
Temperature: 150 °C

Procedure:
A mixture of 2.4 g of 4-chloro-l-(2-pyridyl-methyl)-1H-imidazo[4,5-c]quinoline and 50 mL of 15% ammonia in methanol was placed in a bomb and heated at 150° C. for 6 hours. After cooling, the reaction mixture was filtered. The solid was slurried with aqueous sodium bicarbonate, collected and dried to provide 1.9 g of crude product. The crude product was recrystallized from 350 mL of ethanol to provide 1.25 g of a solid, m.p. 278°-284° C. The mother liquor was concentrated to a volume of 50 mL to provide a second crop of 0.32 g, m.p. 275°-281° C. The two crops were combined for analysis. Analysis: Calculated for C16H13N5 : % C, 69.8; % H, 4.8; % N, 25.4; Found % C, 69.7; % H, 4.8; N, 25.2.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[CH3:15][N:14]1[C:10]([C:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:17][OH:18])=[N:11][N:12]=[N:13]1
Reactant: Cc1cccnc1C(=O)c1nnnn1C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccnc1C(=NO)c1nnnn1C
Yield: 88 %

Procedure:
A solution of (3-methylpyridin-2-yl(1-methyltetrazol-5-yl)methanone (2.8 g, 13.8 mmol) and hydroxylamine hydrochloride (2.4 g, 34.4 mmol) in pyridine (30 ml) is stirred three hours at 50° C. and overnight at room temperature. The solvent is evaporated and water is added to the crude mixture. The resulting suspension is filtered. The solid is washed with water and dried to give 2.65 g of 1-methyl-5-[(3-methylpyridin-2-yl)carbohydroximoyl]tetrazole [yield 88.1%; 1H-NMR (DMSO-d6) δppm: 2.6 (s, 3H), 4.02 (s, 3H), 7.35 (dd, 1H), 7.82 (d, 1H), 8.34 (d, 1H), 13.1 (s, 1H)].
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3]1.[H-].[Na+].Cl[C:24]1[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=1>>[O:20]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[N:18]=[CH:17][N:16]=[C:15]([NH:19][C:24]4[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=4)[CH:14]=3)[CH2:11][CH2:12]2)[CH2:3]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1cc(N2CCN(C3CCS(=O)(=O)C3)CC2)ncn1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCN(C4CCS(=O)(=O)C4)CC3)ncn2)s1

Procedure:
6-[4-(1,1-Dioxidotetrahydrothien-3-yl)piperazin-1-yl]pyrimidin-4-amine 39-2 (0.30 g, 1.01 mmol), sodium hydride (0.081 g, 2.02 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.14 g, 1.01 mmol) were treated as in Scheme 4 above. The product was purified on a C18 column. Hi-Res MS: calc: 406.1114 found: 406.1105. 1H-NMR: 8.46(s, 1H); 8.01(s, 1H); 6.24(s, 1H); 3.86(br s, 6H); 3.59(m, 1H); 3.39(m, 1H); 3.27(m, 1H); 3.17(complex, 4H); 2.70(m, 1H); 2.29(m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:16](=[O:17])[N:15]([CH3:18])[C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=3[S:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:11]1([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16](=[O:17])[N:15]([CH3:18])[C:14]2[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=2[S:12]1
Reactant: BrCCCCBr
Reactant: COc1ccc(C2Sc3ccccc3N(C)C2=O)cc1OC
Product: COc1ccc(C2(CCCCBr)Sc3ccccc3N(C)C2=O)cc1OC
Yield: 67.2 %

Procedure:
3,4-Dihydro-2-(3,4-dimethoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (5.0 g) and 1,4-dibromobutane (10.3 g) are treated by the similar method as in Example 12 to give 4.8 g (66.9%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>C(#N)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: Oc1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Nc1ccc2ccc(Oc3cccc(F)c3)nc2n1
Temperature: 4 °C
Yield: 64.5 %

Procedure:
The procedure is similar to that described in Example 37, but starting with 2-amino-7-chloro-1,8-naphthyridine (18 g), 3-fluorophenol (44.8 g) and potassium hydroxide pellets (13.2 g; 85% purity). After treatment with caustic soda and washing, the product produced (23.5 g; m.p. 161° C.) is dissolved in boiling acetonitrile (120 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). 2-Amino-7-(3-fluorophenoxy)-1,8-naphthyridine (16.5 g) is produced, m.p. 165° C.