Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH:17]1[O:19][CH2:18]1>C1C=CC=CC=1.CCCCCC>[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH:17]([OH:19])[CH2:18][NH:13][CH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: Cc1ccccc1C1CO1
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COc1ccc(CCNCC(O)c2ccccc2C)cc1OC
Yield: 36.2 %

Procedure:
Homoveratrylamine (13.6 g, 0.0753 mole) and o-methylstyrene oxide (10.1 g, 0.0753 mole) were stirred at 100° under argon for 16 hours and then diluted with benzene and hexane and cooled in ice. The solid which precipitated was filtered and recrystallized from benzene-hexane to give 8.6 g (36%) of 2-methyl-α-[N-(3,4-dimethoxyphenethyl)aminomethyl]benzyl alcohol, mp 91°-94°.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Cl:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][Cl:12].C(N(CC)CC)C.Cl.C(N(CC)CC)C>C1COCC1>[Cl:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][Cl:12])[P:1]([Cl:5])([Cl:3])=[O:2]
Reactant: ClCCNCCCl
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=P(Cl)(Cl)N(CCCl)CCCl

Procedure:
Phosphorous oxychloride (0.15 mol) in 100 ml. THF are mixed dropwise at 10° C. with bis-chloroethylamine (0.1 mol) in 100 ml. THF and triethylamine (0.15 mol). After ending of the reaction (TLC verification), triethylamine hydrochloride is filtered off and the filtrate, after the addition of 50 ml. toluene, evaporated. The oily residue is immediately further reacted.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=O)[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1.O=P(Cl)(Cl)[Cl:24]>>[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:24])=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2cc(Br)ccc12
Temperature: 115 °C
Reaction time: 3 h

Procedure:
20.4 ml (0.12 mol) of N-ethyldiisopropylamine were slowly added to a suspension of 55.0 g (0.24 mol) of 7-bromo-3H-quinazolin-4-one in 300 ml of phosphorus oxytrichloride. The reaction mixture was stirred at 115° C. for 3 h and subsequently allowed to come to room temperature. Conventional work-up gave 48.0 g of 7-bromo-4-chloroquinazoline; HPLC/MS (M+H)+=244 as solid.
Reaction SMILES: [ClH:1].CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.N1C=CC=CC=1.Cl.[CH2:42]1C[O:45][CH2:44][CH2:43]1.CN(C=O)C>>[ClH:1].[F:32][C:31]([F:33])([F:34])[C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:44](=[O:45])[CH:43]=[CH2:42])[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(C(F)(F)F)c3)c2c1
Reactant: C1CCOC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncnc(Nc3cccc(C(F)(F)F)c3)c2c1
Temperature: 0 °C
Yield: 45 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (212 mg, 1.1 mmol) was added to a solution of 6-amino-4[(3-(trifluoromethyl)phenyl)-amino]quinazoline (153 mg, 0.5 mmol) acrylic acid (73 mg, 1.0 mmol) and pyridine (206 mg, 2.5 mmol) in THF/DMF (4:1, 2.5 mL), stirred under nitrogen at 0° C. After 15 minutes the reaction mixture was stirred at 25° C. for 1 hour, and then recooled to 0° C. Dilute hydrochloric acid (0.5 M, 10 mL) was added, and after 15 minutes the precipitate was collected by Buchner filtration. The residue was rinsed with water (5 mL) and ether (2×5 mL) and dried in a vacuum oven at 75° C. overnight to give N-[4-[(3-(trifluoromethyl)phenyl)amino]quinazolin-6-yl]acrylamide hydrochloride (87 mg, 45%) as a light greenish solid, mp 195-199° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[S:18][CH2:17][CH2:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][C:13]=3[CH:23]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[S:18][CH2:17][CH2:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[CH:23]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(OC)cc3)ccc2SCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3)cc1
Reaction time: 18 h
Yield: 106.2 %

Procedure:
To a solution of methyl 7-(4-methoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (0.50 g) in ethanol/THF (10/10 ml) was added at room temperature 1N sodium hydroxide solution (2 ml), and the mixture was stirred for 18 hours. To the mixture was added 1N hydrochloric acid (2 ml). Under reduced pressure, the mixture was concentrated. To the mixture was added water, and the precipitates were collected by filtration, which were washed with 2-propanol, diethylether and hexane to give pale yellow solid of 7-(4-methoxyphenyl)-2,3-dihydro-1-benzo-thiepine-4-carboxylic acid (508 mg). This compound was used for the following reaction, without subjecting further purification.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH:28]=[CH2:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](CO)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:31]1>>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH2:28][CH2:29][OH:31])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: C[C@]12CCCCC1[C@@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C[C@]12CCCCC1[C@@H](CCO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Yield: 96 %

Procedure:
17,17-Bis(ethylendioxy)-6α-(2-hydroxyethyl)androstane was prepared in 96% yield from 3,3:17,17-bis(ethylendioxy)-6α-vinylandrostane by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6α-hydroxymethyl-androstane (Prepn. 14). The crude was purified by flash chromatography (SiO2, n-hexane/acetone 80/20). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.25 (1H, t), 3.86-3.70 (8H, m), 3.35 (2H, m), 1.91-0.42 (23H, m), 0.75 (3H, s), 0.74 (3H, s).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:33][CH2:34][CH3:35])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].OO.O.C(=O)([O-])[O-:40].[K+].[K+]>CS(C)=O>[C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][N:13]([CH2:33][CH2:34][CH3:35])[CH:9]3[CH2:10][C:11]4[CH:12]=[C:3]([C:1]([NH2:2])=[O:40])[CH:4]=[CH:5][C:6]=4[CH2:7][CH2:8]3)=[O:32])=[CH:21][CH:22]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: CCCN(CCCCNC(=O)c1ccc(-c2ccccc2)cc1)C1CCc2ccc(C#N)cc2C1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCN(CCCCNC(=O)c1ccc(-c2ccccc2)cc1)C1CCc2ccc(C(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
To a solution of 7-cyano-N-(4-(4-phenylbenzoylamino)butyl)-2-(R,S)-propylamino-1,2,3,4-tetrahydronaphthalene (0.983 g, 2.11 mmol) in dimethyl sulfoxide (4 ml) at 15° C. was added a solution of hydrogen peroxide in water (27.5% w/v; 0.26 ml; 2.12 mmol) followed by anhydrous potassium carbonate (0.42 g, 3.06 mmol). The mixture was stirred for 6 h at room temperature, then poured into water (100 ml) and the resulting solid filtered off to give the title compound (0.84 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:5]2.[C:24]([C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1)(=[O:26])[CH3:25]>>[C:24]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH:15][CH2:14][CH2:13][CH2:12][N:7]2[CH:6]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[O:35])[CH:30]=[CH:31][CH:32]=1)(=[O:26])[CH3:25]
Reactant: NCCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Reactant: CC(=O)c1cccc(N=C=O)c1
Product: CC(=O)c1cccc(NC(=O)NCCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 238-b) as a starting material, and using 3-acetylphenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH2:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH3:40]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 26.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.100 g, 0.194 mmol) obtained in step 2 and ethanesulfonamide (0.105 g, 0.969 mmol), the title compound (0.031 g, 27%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[CH:27]=[CH:26][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[C:18]3[C:24]#[N:25])=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[C:24]([C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([CH2:14][CH2:13][NH:12][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([C:3]([CH3:5])([CH3:4])[CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:27][CH:26]=3)[CH:16]=2)[NH:20][CH:19]=1)#[N:25]
Reactant: CC(C)(CN)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(CNS(C)(=O)=O)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
To a solution of 4-[2-amino-1,1-dimethyl-ethyl]-N-[2-(3-cyano-1H-indol-5-yl)-ethyl]-benzamide (97 mg, 0.27 mmol) (reference example 105) in CH2Cl2 (1 ml) was added pyridine (24 μL, 0.30 mmol) and methanesulfonyl chloride (23 μL, 0.30 mmol). The reaction was stirred for 5 min then concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 8% 7M NH3 in CH3OH/CH2Cl2 to give 95 mg of product. MS (ion spray) m/z 439 (M+H)+.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:37])C.Cl.O>CC(C)=O>[CH:4]([CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:37])=[O:3]
Reactant: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of 4.32 g of (RS)-1-(2,2-diethoxyethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in 50 ml of acetone was added 5 ml of 2N hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the thus formed precipitate was collected by filtration and washed with ethyl ether to obtain 2.94 g (79%) of the title compound.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][C:37]1[N:38]=[CH:39][S:40][C:41]=1[CH:42]=[O:43].C([Li])(CC)C>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([CH:42]([C:41]2[S:40][CH:39]=[N:38][C:37]=2[CH3:36])[OH:43])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ncsc1C=O
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Agent: [Li]C(C)CC
Product: Cc1ncsc1C(O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3, 1.0 g, 2.02 mmol), 4-methyl-1,3-thiazole-5-carbaldehyde and sec-butyllithium
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[OH:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:6][O:7][C:8]([C:9]1[C:10]2[O:16][CH2:2][C:3](=[O:4])[NH:15][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:17]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1OCC(=O)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At RT chloro-acetyl chloride (29.0 mmol) is added dropwise to a solution of 3-amino-2-hydroxy-benzoic acid methyl ester (26.4 mmol) in DMF (100 mL). After 20 min K2CO3 (126 mmol) is added portionwise, the mixture is stirred for 16 h at RT and the solvents are removed in vacuo. Water and DCM are added, the layers are separated and the organic layer is washed with brine and dried over Na2SO4. The solvents are removed in vacuo to give a crude product which is used without further purification. LC-MS: tR=0.68 min; [M+H]+=208.0.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1>CS(C)=O.O>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cccc2)c(F)c1
Temperature: 90 °C
Yield: 97 %

Procedure:
To a solution of 1,2-difluoro-4-nitrobenzene (1.59 g, 10 mmol) in DMSO (15 mL) were added K2CO3 (3.04 g, 22 mmol) and pyrrole (0.74 g, 11 mmol) with stirring. The reaction mixture was heated at 90° C. for 18 h, and cooled to rt. The mixture was diluted with water (50 mL), filtered and the filter cake was dried to give the title compound as a yellow solid (2.00 g, 97%).
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:10])(=[O:9])[N:8]=[CH:7][CH:6]=[CH:5][NH:4]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]I)[CH2:27][CH2:26]1>CN(C)C=O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][N:8]2[CH:7]=[CH:6][CH:5]=[N:4][S:3]2(=[O:10])=[O:9])[CH2:27][CH2:26]1
Reactant: COc1cc2ncnc(N3CCC(CI)CC3)c2cc1OC
Reactant: O=S1(=O)N=CC=CN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCC(CN4C=CC=NS4(=O)=O)CC3)c2cc1OC

Procedure:
Sodium hydride (0.20 g. of a 50% dispersion in oil) was added to a stirred solution of 2H-1,2,6-thiadiazine-1,1-dioxide (0.56 g) in dimethylformamide (4 cm3). After 0.5 hours 1-(6,7-dimethoxyquinazolin-4-yl)-4-iodomethylpiperidine (0.70 g) was added and the mixture was warmed at 70° for 10 hours. The solvent was removed in vacuo, water was added and the mixture was extracted with chloroform (4×20 cm3). The dried (MgSO4) extracts were evaporated and the residue was chromatographed on silica (MK 60.9385) eluting with methanol:ethyl acetate, 1:19, to give a foam. Crystallisation from ethyl acetate afforded 1-(6,7-dimethoxyquinazolin-4-yl)-4-(1,1-dioxo-1,2,6-thiadiazin-2-yl)methyl piperidine as white microcrystals, m.p. 173°-174°, (0.27 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[CH2:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C=Cc1cccc2oc(C(=O)OCC)c(C)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cccc(CC)c2c1C

Procedure:
To a solution of 0.40 g (1.74 mmol) of 3-methyl-4-vinylbenzofuran-2-carboxylic acid ethyl ester in 25 mL of ethyl acetate under nitrogen was added 0.050 g of 10% palladium on carbon. The reaction was shaken on a Parr hydrogenator under 40 psi of hydrogen for 4 h. The reaction was then filtered through a pad of celite. The celite was washed with an additional 150 mL of ethyl acetate and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:30) to provide 0.395 of 3-methyl-4-ethylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CN(CC1SC=C(CSC[CH2:27][NH:28][C:29]2[C:33](OC)=[N:32][S:31](=[O:36])[N:30]=2)N=1)C.CN>CO>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:33]2[C:29]([NH:28][CH3:27])=[N:30][S:31](=[O:36])[N:32]=2)[N:9]=1)[CH3:1]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: COC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1
Agent: CN
Solvent: CO
Product: CNC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
When a methanol suspension of 3,4-dimethoxy-1,2,5-thiaziazole 1-oxide [prepared in Example 4, Step A] is reacted with an equimolar amount of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine [prepared in Example 33, Step E] and the resulting 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1-oxide is treated with methylamine, the title compound is thereby produced.
Reaction SMILES: [CH:1]1([CH2:11][CH2:12][C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:1]1([CH2:11][CH2:12][CH2:13][OH:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1
Reactant: O=C(O)CCC1OCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCC1OCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(isochroman-1-yl)propionic acid (LXXXVII, 0.5054 g, 2.45 mmol) in THF (2.8 ml) is added to an ice-cooled slurry of lithium aluminum hydride (0.1021 g, 2.69 mmol) in THF (3 ml). After the mixture had stirred for 30 min at 0°, it is quenched slowly with water (0.10 ml) water and allowed to stir for 15 min. An aqueous sodium hydroxide solution (15%, 0.10ml) is added and again the reaction stirred 15 min. After a final addition of water (0.3 ml) the solids are removed by filtration and washed with ether. The filtrate is washed with saline, dried over magnesium sulfate and concentrated to dryness. The crude product is chromatographed on silica gel eluting with methanol/dichloromethane (2/98). The appropriate fractions are pooled and concentrated to give 3-(isochroman-1-yl)propanol (LXXXVIII), NMR (CDCl3) 1.73, 1.92, 2.11, 2.34, 2.68, 3.03, 3.66, 3.78, 4.17, 4.82 and 7.15 δ.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]([CH:30]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:31]OC3C=CC=CC=3F)[C:28]3[CH:46]=[C:47]([F:51])[C:48]([F:50])=[CH:49][C:27]=3[N:26]=2)=[CH:21][CH:20]=1>CN(C)C=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([S:1][CH2:31][CH:30]([N:29]2[C:28]3[CH:46]=[C:47]([F:51])[C:48]([F:50])=[CH:49][C:27]=3[N:26]=[C:25]2[C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)=[CH:11][CH:10]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3ccccc3F)C3CCCCC3)c2cc1F
Reactant: COC(=O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 74 mg (0.44 mmol) methyl 4-mercaptobenzoate in 3 ml N,N-dimethylformamide was added 61 mg (0.44 mmol) potassium carbonate at 0° C. The reaction mixture was stirred for 15 min. and then 200 mg (0.44 mmol) 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 34, intermediate) was added at the same temperature. The cooling bath was removed and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture was poured on 10% aqueous 30 ml citric acid and 30 ml ethyl acetate and the layers were separated. The aqueous layer was extracted a second time with 30 ml ethyl acetate. The combined organic layers were washed with 30 ml brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the desired compound as a colorless solid (65%). MS (Turbo Spray) m/z=541.2 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7](O)=O)[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:6]([CH2:7][Cl:15])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cl)cc1C(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1CCl

Procedure:
To a solution of 5-chloro-o-anisic acid (50 g) in toluene (100 mL) was added thionyl chloride (50 mL). The reaction mixture was heated under reflux for 2 hrs and distilled using a short path distillation apparatus to give 5-chloro-o-anisyl chloride, which was used in the next step. To a solution of 2-amino-2-methyl-1-propanol (38 mL) in dichloromethane (200 mL) was added a solution of 5-chloro-o-anisyl chloride in dichloromethane (150 mL) dropwise. The reaction mixture was stirred at ambient temperature for 1 hr, dichloromethane was added and the mixture was washed with 2 N hydrochloric acid. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give N-(2-(1-hydroxy-2-methylpropyl)-5-chloro-2-methoxy benzamide, which was used in the next step. To N-(2-(1 -hydroxy-2-methylpropyl)-5-chloro-2-methoxy benzamide was added thionyl chloride (40 mL) at 0° C. The reaction mixture was stirred for 30 min, warmed to ambient temperature, diluted with diethyl ether (200 mL), and the mixture was stirred for 10 mins. The mixture was decanted, 10% sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to afford 41 g (64%) of product, mp 50-51° C.