Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH3:3].[NH2:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[NH:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])=[CH:21][CH:20]=[C:19]([Br:30])[CH:18]=2>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[Br:30][C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[N:24]([CH2:25][C:26]([CH3:27])([OH:28])[CH3:29])[C:1]([CH2:2][CH3:3])=[N:13][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1
Reactant: CCOC(CC)(OCC)OCC
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Br)ccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
Triethyl orthopropionate (12.9 g, 73.2 mmol) and pyridine hydrochloride (220 mg) were added to a solution of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (22.1 g, 70.6 mmol) in anhydrous toluene (300 mL), and the reaction was heated at reflux for three hours. The reaction was allowed to cool to ambient temperature and stand overnight; a precipitate formed. The precipitate was isolated by filtration, washed with toluene, and air-dried to provide 18.42 g of 1-(7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as beige crystals.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)=[NH:8])C>C(O)=O>[Br:15][C:11]1[CH:10]=[C:9]([C:7]2[NH:8][CH:4]=[CH:5][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(CNC(=N)c1cccc(Br)c1)OCC
Solvent: O=CO
Product: Brc1cccc(-c2ncc[nH]2)c1

Procedure:
A solution of N-[2,2-bis(ethyloxy)ethyl]-3-bromobenzenecarboximidamide (2.85 g; 9.04 mmol; Step 2 above) in HCO2H (15 mL) was heated at 80° C. for 1 h and concentrated in vacuo (2×PhMe chase). The residue was purified by flash chromatography (MeOH/NH4OH/CH2Cl2), affording the title compound as a light pink solid. LC/MS (method A) tR 1.19 min, m/z 223, 225 (M+H, Br isotopes).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Cl.[C@H:20]12[CH2:26][C@H:23]([NH:24][CH2:25]1)[CH2:22][O:21]2.CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:25][C@@H:20]3[CH2:26][C@H:23]2[CH2:22][O:21]3)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C2CCc3c2nc(Cl)nc3N2C[C@@H]3C[C@H]2CO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (200 mg, 0.706 mmol) in MeOH (7064 μL) was added (1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane monohydrochloride (115 mg, 0.848 mmol) and DIPEA (271 μL, 1.554 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was then concentrated in vacuo. The resulting oil was purified by flash chromatography (Silica, EtOAc/Hexanes) to give (1S,4S)-5-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (148 mg, 0.428 mmol, 60.6% yield). LC-MS (M+H)+=346.1. 1H NMR (500 MHz, MeOD) δ ppm 7.12-7.21 (2 H, m), 7.00-7.08 (2 H, m), 5.11-5.21 (1 H, m), 4.69-4.74 (1 H, m), 4.15-4.26 (1 H, m), 3.88-3.94 (2 H, m), 3.68-3.86 (2 H, m), 3.11-3.21 (1 H, m), 2.56-2.69 (1 H, m), 1.92-2.11 (2 H, m), 1.24-1.42 (2 H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[CH3:12])[CH3:2].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:7][C:6]=1[CH3:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(O)cc1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 18 g (100 mmol) of 4-hydroxy-2-methyl-benzoic acid ethyl ester (prepared according to Sen, et. al. (1987), Indian J. Chem. Sec B, 26: 679-682), 10.2 g (150 mmol) of imidazole, and 17.2 g (115 mmol) of tert-butyldimethylsilyl chloride in 110 mL of anhydrous DMF was stirred for 24 hours at room temperature. The reaction was diluted with water and extracted with ethyl acetate. The organic fraction was washed with water, 0.1 N HCl, and brine, then dried over anhydrous magnesium sulfate and concentrated to 28.8 g of the title compound; MS (ESI+): m/z 295.5 (M+1)
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=[O:11])[CH3:8])[CH3:3].C(O)(=O)/C=C(/CCC=C(C)C)\C>>[CH3:3][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:1]
Reactant: CC(C)=CCCC(C)=CC=O
Agent: CC(C)=CCC/C(C)=C/C(=O)O
Product: CC(C)=CCC/C(C)=C/CO

Procedure:
For example, K. C. Guven et al., in Parfumerie und Kosmetik 59, 263 (1978), showed that Candida krusei failed to oxidize citral into geranic acid, but produced geraniol instead.
Reaction SMILES: [CH2:1]([C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.[H][H]>[Pd]>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH2:22][N:11]2[C:10]3[N:9]=[C:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[NH:16][C:15]=3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12]2=[O:21])=[CH:29][CH:28]=1
Reactant: [H][H]
Reactant: CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By methods well known in the art, 8-benzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine (9) is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-benzyl-1-propylxanthine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.O=S(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>CN(C=O)C.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([NH:27][CH:24]2[CH2:26][CH2:25]2)=[O:9])[CH:5]=1
Reactant: NC1CC1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(C(=O)NC2CC2)c1
Temperature: 80 °C

Procedure:
A solution of 0.5 g (2.77 mmol) isophthalic acid mono methyl ester, 5 ml toluene and 0.8 ml SOCl2 is treated with one drop DMF and heated to 80° C. till the evolution of gas ceases. After cooling down the mixture is evaporated, dissolved in 2 ml DCM and added to an at 0° C. stirred mixture of 5 ml 10% aqueous Na2CO3, 0.21 ml (3.0 mmol) cyclopropyl amine and 5 ml DCM. After 1 h the layers are separated and the organic layer is washed with 1 N HCl, brine, dried with sodium sulfate and evaporated. The crude product is crystallized (EtOAc, hexane) to yield N-cyclopropyl-isophthalamic acid methyl ester as off-white crystals.
Reaction SMILES: C[C:2]([CH3:5])([O-])[CH3:3].[K+].[CH3:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:17].C(Br)C#C>CN(C)C=O>[CH3:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:5]=[CH:2][C:3]=2[N:10]([CH2:11][C:16]#[CH:15])[C:9]1=[O:17]
Reactant: CC(C)(C)[O-]
Reactant: Cn1c(=O)[nH]c2ccccc21
Agent: C#CCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCn1c(=O)n(C)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
potassium tert.-butoxide, 2.1 g (18.5 mmol). was added to a solution of 2.5 g (16.9 mmol) of 1,3-dihydro-1-methyl-2H-benzimidazol-2-one in 25 ml of dimethylformamide. After stirring under nitrogen for 15 minutes, 2.21 g (18.5 mmol) of propargyl bromide was added and the mixture was stirred at room temperature for 30 minutes. It was diluted with ice-water and the precipitate was filtered off washed with water and sucked dry. The crude product was passed over silica gel using 10% (v/v) of ethyl/acetate in methylene chloride for elution. Crystallization from ethyl acetate/hexane gave colorless crystals of 1,3-dihydro-1-methyl-3-(2-propynyl)-2H-benzimidazole-2-one with m.p. 110°-112°.
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][O:27]C4CCCCO4)=[O:25])=[CH:18][CH:17]=3)[CH2:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:36]>CO>[ClH:36].[ClH:36].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][OH:27])=[O:25])=[CH:18][CH:17]=3)[CH2:11]2)=[CH:34][CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN2CC[C@@H](Nc3ccc(/C=C/C(=O)NOC4CCCCO4)cn3)C2)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1ccc(CN2CC[C@@H](Nc3ccc(/C=C/C(=O)NO)cn3)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (2E)-3-(6-{[(3R)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (270 mg) was suspended in methanol (1 mL) and to this suspension was added hydrogen chloride in methanol solution(10%, 3 mL). The mixture was stirred at ambient temperature for 15 minutes and concentrated in vacuo. The residual solid was triturated with acetonitrile to give (2E)-3-(6-{[(3R)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide dihydrochloride (228 mg) as a pale tan solid.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[N:24]=[C:23]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)[CH:22]=[CH:21][CH:20]=3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CCO.CCOC(C)=O>[S:26]1[CH:27]=[CH:28][N:29]=[C:25]1[C:23]1[N:24]=[C:19]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][CH:10]=[C:9]3[OH:8])[CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(COc2ccnc3ccc(-c4cccc(-c5nccs5)n4)cc23)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1ccnc2ccc(-c3cccc(-c4nccs4)n3)cc12
Reaction time: 72 h
Yield: 88 %

Procedure:
To a solution of 2-(6-(4-(benzyloxy)quinolin-6-yl)pyridin-2-yl)thiazole (1.0 equiv.) in 1:1 EtOH/EtOAc, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 72 hours. At this time the mixture was filtered through a pad of celite eluting with EtOAc. The volatiles were removed in vacuo yielding 6-(6-(thiazol-2-yl)pyridin-2-yl)quinolin-4-ol (88%). LCMS (m/z): 305.9 (MH+); LC Rt=2.57 min.
Reaction SMILES: [Na].[NH2:2][C:3]1[N+:8]([O-:9])=[C:7]([NH2:10])[CH:6]=[C:5]([O:11][C:12]2C=CC(Cl)=CC=2Cl)[N:4]=1>CO>[NH2:2][C:3]1[N+:8]([O-:9])=[C:7]([NH2:10])[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1
Reactant: Nc1cc(Oc2ccc(Cl)cc2Cl)nc(N)[n+]1[O-]
Agent: [Na]
Solvent: CO
Product: COc1cc(N)[n+]([O-])c(N)n1

Procedure:
1.8 g of sodium are dissolved in 150 ml of methanol. 15 of 2,4-diamino-6-(2,4-dichlorophenoxy)pyrimidine 3-oxide are added and the reaction mixture is refluxed for 15 days.
Reaction SMILES: OCCCCCCOC1C=CC(C#CC2C=C3C(=CC=2)C=C(OCCCCCCOC(=O)C=C)C=C3)=CC=1.[CH2:39]([O:44][C:45](=[O:74])[C:46]1[CH:51]=[C:50](OC(=O)C2C=CC(OCCCCCCOC(=O)C=C)=CC=2)[CH:49]=[CH:48][C:47]=1O)[CH2:40][CH2:41][CH2:42][CH3:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:39]([O:44][C:45](=[O:74])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(O)c(C(=O)OCCCCC)c2)cc1
Agent: C=CC(=O)OCCCCCCOc1ccc2cc(C#Cc3ccc(OCCCCCCO)cc3)ccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of acrylic acid 6-{6-[4-(6-hydroxyhexyloxy)phenylethynyl]-naphthalen-2-yloxy)hexyl ester (1.05 g), 5-[4-(6-acryloyloxyhexyloxy)benzoyloxy]-2-hydroxybenzoic acid pentyl ester (1.12 g) and triphenylphosphine (0.59 g) in tetrahydrofuran (20 ml) was added under argon and in a dropwise fashion diethyl azodicarboxylate (DEAD, 0.39 g). Upon complete addition, the reaction mixture was stirred at room temperature overnight, and the solvent was then removed under reduced pressure to give a residue which was purified by flash chromatography using a silica-gel column and cyclohexane/ethyl acetate (8/2) as eluent to give 0.66 g of 5-[4-(6-acryloyloxyhexyloxy)benzoyloxy]-2-[6-[4-[6-(6-acryloyloxyhexyloxy)naphtha len-2-ylethynyl]phenoxy]hexyloxy]benzoyloxy]benzoic acid pentyl ester as white crystalline material. K 39° C. N 113° C. I.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([CH2:12][CH2:13][NH2:14])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[C:1]1([C:7]2[N:11]=[C:10]([CH2:12][CH2:13][NH:14][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:32])([F:31])[F:15])[O:21][N:20]=4)[CH:23]=3)[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCc1nc(-c2ccccc2)n[nH]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1nc(-c2ccccc2)n[nH]1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 21 %

Procedure:
This compound was synthesized from 2-(3-phenyl-1H-1,2,4-triazol-5-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (17 mg, yield 21%). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.21-8.19 (d, J=7.8 Hz, 1H), 8.06-8.04 (t, J=7.8 Hz, 1H), 8.01-7.99 (m, 2H), 7.89 (m, 1H), 7.58-7.54 (d, J=7.8 Hz, 1H), 7.40-7.39 (m, 3H), 4.00-3.95 (q, J=5.9 Hz, 2H), 3.24-3.21 (d, J=6.1 Hz, 2H). MS (ESI) m/z: Calculated for C20H15F3N6O2: 428.12. found: 429.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3]([N:5]=[C:6]=[S:7])=[O:4].[NH3:9]>C(Cl)Cl>[CH3:1][N:2]([CH3:8])[C:3]([NH:5][C:6]([NH2:9])=[S:7])=[O:4]
Reactant: CN(C)C(=O)N=C=S
Reactant: N
Solvent: ClCCl
Product: CN(C)C(=O)NC(N)=S
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 65 parts of dimethylcarbamoylisothiocyanate (a compound of formula VI) in 350 parts methylene chloride are added within 10 minutes at 0° C, 50 parts of conc. aqueous ammonia with good agitation. The resulting slurry of crystals is stirred for an additional 15 minutes at 0° C and then filtered to give 70 parts of 1,1-dimethyl-4-thiobiuret (a compound of formula VII), m.p. 184°-185° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][NH:4][C:5](=[O:7])[CH:6]=1.Br[CH2:9][CH3:10].C(=O)(O)[O-].[Na+]>>[CH2:9]([N:4]1[C:5](=[O:7])[CH2:6][C:2]([CH3:1])=[N:3]1)[CH3:10]
Reactant: CCBr
Reactant: Cc1cc(=O)[nH][nH]1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN1N=C(C)CC1=O
Temperature: 130 °C

Procedure:
A mixture of 49 g 3-methyl-3-pyrazolin-5-one and 60.0 g bromoethane was sealed in a glass pressure tube and heated in an oil bath at 130° C. for 40 hours. After cooling, the tube was opened and the contents were poured into 200 g ice-water. Sodium bicarbonate (42.00 g) was added in small portions with stirring. The resulting mixture was stirred and heated to 100° C. for 1 hour, cooled to room temperature, and extracted with 10×50 ml portions of chloroform. The combined extracts were dried over anhydrous calcium chloride, evaporated under reduced pressure and the residue recrystallized from ethanol to give 20.1 g as colorless prisms, m.p. 112°-113° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:14])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])(C)(C)C.[C:16]([OH:22])([C:18]([F:21])([F:20])[F:19])=[O:17]>C(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:16]([OH:22])=[O:17].[CH3:14][C@@H:8]([NH2:7])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: C[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)CC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ((R)-1,3,3-trimethyl-butyl)-carbamic acid tert-butyl ester (35 mg, 0.163 mmol) in CH2Cl2 (1 mL) was added TFA (0.125 mL, 1.625 mmol). The reaction mixture was stirred at RT for 2 h and concentrated to give the desired material which was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.66 (bs, 3H), 3.25 (m, 1H), 1.50 (dd, 1H), 1.38 (dd, 1H), 1.23 (d, 3H), 0.93 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([N+:22]([O-])=O)[CH:5]=1.[H][H]>C(OCC)(=O)C.[Ni]>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([NH2:22])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(C)cc2)c(S(N)(=O)=O)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(Oc2ccc(C)cc2)c(S(N)(=O)=O)c1

Procedure:
45 g of 3-nitro-4-(4'-methylphenoxy)-5-sulphamoylbenzoic acid methyl ester are suspended in 150 ml of ethyl acetate and hydrogenated for 5 hours with Raney nickel at 50° C. and a hydrogen pressure of 100 atmospheres gauge. After cooling, the Raney nickel is separated and the solution is concentrated to dryness. The 3-amino-4-(4'-methylphenoxy)-4-sulphamoylbenzoic acid methyl ester is recrystallised from mthanol/H2O. Crystals melting at 183°-185° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CCCCCBr
Reactant: N#CCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(C#N)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5 g (37.0 mmol) of (4-fluorophenyl)acetonitrile are added dropwise to a suspension of 1.62 g of 60% NaH in 50 ml of DMF cooled to 0° C. After stirring for 30 minutes at 0° C., 4.62 mmol (37.0 mmol) of bromopentane are added dropwise. The reaction medium is stirred for 16 hours at ambient temperature and then treated with ice and extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated under pressure. An orangey-yellow oil is obtained and used as it is in the next stage.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5].[C:15](=S)=[S:16].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[I:14][C:11]1[CH:10]=[C:3]2[C:2](=[CH:13][CH:12]=1)[NH:1][C:15](=[S:16])[N:6]([CH2:7][CH2:8][CH3:9])[C:4]2=[O:5]
Reactant: CCCNC(=O)c1cc(I)ccc1N
Reactant: S=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=S)[nH]c2ccc(I)cc2c1=O
Temperature: 25 °C

Procedure:
To a solution of 2-amino-5-iodo-N-propylbenzamide (1.0 g, 3.1 mmol) and carbon disulfide (0.59 g, 9.38 mmol) in dimethylformamide (3.1 mL) was added potassium carbonate (0.43g, 3.1 mmol). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, and added dropwise to 1N hydrochloric acid (25 mL). The resulting precipitate was filtered, washed with water (2×10 mL), methanol (2×10 mL) and diethyl ether (10 mL), and dried to deliver 1.04 g of the title compound, m.p. 267-269° C.; 1H NMR (300 MHz, Me2SO-d6): δ0.90 (t,3H); 1.68 (m,2H); 4.33 (t,2H); 7.18 (d,1H); 8.04 (dd,1H); 8.19 (d, 1H); 12.98 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[CH2:16][NH:17][C:18]1[C:27]2[S:26][CH2:25][C:24](=[O:28])[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.CI.[C:34]([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CN(C=O)C>[CH3:34][N:23]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:17][CH2:16][C:15]3[CH:29]=[CH:30][CH:31]=[C:13]([O:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH:14]=3)[C:27]=2[S:26][CH2:25][C:24]1=[O:28]
Reactant: O=C([O-])[O-]
Reactant: O=C1CSc2c(NCc3cccc(OCc4ccc5ccccc5n4)c3)cccc2N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)CSc2c(NCc3cccc(OCc4ccc5ccccc5n4)c3)cccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.3 %

Procedure:
After a mixture of 1.690 g (3.95 m-mol) of 8-[3-(2-quinolinylmethoxy)benzylamino]-3,4-dihydro-2H-1,4-benzothiazin-3-one obtained in Example 95, 0.673 g (4.74 mmol) of CH3I, 1.311 g (9.5 mmol) of K2CO3, 0.129 g (0.4 mmol) of (n-Bu)4NBr and 50 ml of DMF was stirred at room temperature for 3 days, the solvent was distilled off under reduced pressure. Water was added to the residue, followed by extraction with CHCl3. The extract was washed with water, dried over MgSO4 and then concentrated. The residue was subjected to chromatography on a silica gel column. Subsequent to elution with CHCl3, recrystallization was conducted from an acetone-n-hexane mixed solvent, whereby 1.000 g of the title compound was obtained (yield: 57.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([OH:40])[CH2:37][NH:38][CH3:39])=[CH:32][CH:31]=1)[CH3:28].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:38]([CH2:37][CH:36]([C:33]4[CH:32]=[CH:31][C:30]([CH2:29][N:27]([CH3:26])[CH3:28])=[CH:35][CH:34]=4)[OH:40])[CH3:39])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CNCC(O)c1ccc(CN(C)C)cc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccc(CN(C)C)cc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 7 h
Yield: 25.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-{4-[(dimethylamino)methyl]phenyl}-2-(methylamino)ethanol (Preparation 50) (89 mg, 0.43 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (7 mL). The resulting milky mixture was concentrated to dryness. The residue was purified with a silica gel chromatotron plate to yield the title compound (36 mg) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[C:5]=1[O:13][CH3:14].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18]Br.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[C:5]=1[O:13][CH3:14])[CH3:1]
Reactant: COC(CBr)OC
Reactant: CNCc1ccc2c(c1OC)OCO2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1c(CN(C)CC(OC)OC)ccc2c1OCO2
Temperature: 25 °C
Yield: 92 %

Procedure:
0.98 g of N-methyl-(2-methoxy-3,4-methylenedioxybenzylamine obtained in Example 14, 0.93 g (1.1 equivalent) of bromoacetaldehyde dimethylacetal and 0.76 g (1.5 equivalent) of triethylamine as base were mixed in 7.3 ml of toluene and heated under reflux for 4 hours. On cooling the reaction mixture to room temperature, the deposited salts were filtered out and the toluene layer was analyzed to show that 1.302 g of the desired N-(2-methoxy-3,4-methylenedioxybenzyl)-N-methylaminoacetaldehyde dimethylacetal was obtained. Yield 92%. Because 0.25 g of excessive triethylamine was present in the toluene layer, a toluene solution of the desired N-(2-methoxy-3,4-methylenedioxybenzyl)-N-methylaminoacetaldehyde dimethylacetal was obtained by distilling off excessive triethylamine at atmospheric pressure.