Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][C:11]2[N:21]3[C:22]4[C:17]([CH:18]([SH:23])[CH2:19][CH2:20]3)=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:24]I>O1CCCC1>[CH3:24][S:23][CH:18]1[C:17]2[C:22]3=[C:13]([N:12]=[C:11]([CH2:10][CH2:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:21]3[CH2:20][CH2:19]1)[CH:14]=[CH:15][CH:16]=2
Reactant: CI
Reactant: SC1CCn2c(CCc3ccccc3)nc3cccc1c32
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 60% sodium hydride (245 mg) and anhydrous tetrahydrofuran (20 mL) under an argon atmosphere was added dropwise the solusion of 5,6-dihydro-2-(2-phenylethyl)-4H-imidazo[4,5,1-ij]quinoline-6-thiol (0.45 g) obtained in Example 28 in anhydrous tetrahydrofuran (20 mL) at room temperature. After stirring for 1 hr at room temperature, methyl iodide (0.95 mL) was added dropwise and the mixture was stirred for 30 min. Ice water was added to the reaction solution and stirred; thereafter, the mixture was extracted with ethyl acetate and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to yield the titled compound as colorless crystals (356 mg).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[CH3:27][OH:28]>>[C:1]([O:4][C@@H:5]1[C@H:10]([NH:11][C:12]([O:28][CH3:27])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CO
Product: COC(=S)N[C@H]1[C@@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (1.0 g, 2.57 mmol) in anhydrous methanol (10 mL) was heated to reflux. The reaction was complete after 1 h as determined by TLC. The solvent was removed in vacuo. The product was then purified by flash column silica chromatography using a solvent system of 3:1 hexanes/EtOAc, which provided (2R,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(methoxycarbonothioylamino)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (1.0 g, 92% yield) as a slightly yellow syrup. 1H NMR (500 MHz, CDCl3) δ 2.11 (s, 3H), 2.12 (s, 6H), 3.81 (ddd, 1H), 3.95 (s, 3H), 4.1 (m, 2H), 4.31 (m, 1H), 5.17 (m, 2H), 5.73 (d, 1H, J=8.6 Hz), 6.21 (d, 1H, J=10.0 Hz).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.C(Cl)(Cl)Cl.[Br:33]N1C(=O)CCC1=O>C(#N)C>[Br:33][C:14]1[N:13]=[C:12]([C:15]([NH2:17])=[O:16])[C:11]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=2)=[N:10][C:9]=1[NH:8][C@H:5]1[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]1
Reactant: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)cnc2C(N)=O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(Br)nc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 111) (150 mg), chloroform (40 mL) and acetonitrile (20 mL), N-bromosuccinimide (69 mg) was added and stirred at room temperature for 2 hours. To the reaction liquid, silica gel was added, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform:methanol=10:0:0 to 10:1). The resulting crude product was solidified with ethyl acetate and washed with ethyl acetate to give 6-bromo-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (130 mg) as a light yellow solid.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][CH2:36][S:37][CH3:38])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][CH2:36][S:37][CH3:38])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CSCC[C@H](N)C(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](CCSC)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.90 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 66-2 (7.48 mmol, crude form) as starting materials, respectively 1.17 g (Isomer A, pale yellow amorphous) and 1.49 g (Isomer B, pale yellow amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:41]=[CH:40][C:10]([C:11]([C:13]3[CH:33]=[CH:32][C:16]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=4)=[C:15]([CH2:34][CH2:35][C:36]([O:38]C)=[O:37])[CH:14]=3)=[O:12])=[C:9]([OH:42])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.O1CCCC1.[OH-].[Na+]>[CH:1]1([O:6][C:7]2[CH:41]=[CH:40][C:10]([C:11]([C:13]3[CH:33]=[CH:32][C:16]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=4)=[C:15]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[CH:14]=3)=[O:12])=[C:9]([OH:42])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)/C=C/c1ccc(COc2ccc(C(=O)c3ccc(OC4CCCC4)cc3O)cc2CCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(COc2ccc(C(=O)c3ccc(OC4CCCC4)cc3O)cc2CCC(=O)O)cc1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
1.20 g of ethyl (E)-3-(4-{[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-methoxy-3-oxopropyl)phenoxy]methyl}phenyl)-2-propenoate was dissolved in a mixed solvent of 12 mL of methanol and 12 mL of tetrahydrofuran, to which 2.4 mL of a 20% aqueous solution of sodium hydroxide was added at room temperature, and then this mixture was stirred for one hour at the same temperature. The reaction mixture was concentrated under reduced pressure, to which water was added, and then adjusted to pH 2 with 6M hydrochloric acid. The resultant precipitate was filtered out and washed with water to yield 0.841 g of (E)-3-(4-{[4-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-(3-hydroxy-3-oxopropyl)phenoxy]methyl}phenyl)-2-propenoic acid as light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH2:5].C[O-].[Na+].[CH3:17][CH:18]([SH:20])[CH3:19].Cl>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:5][S:20][CH:18]([CH3:19])[CH3:17]
Reactant: CC(C)S
Reactant: C=C(Cc1ccccc1)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(CSC(C)C)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of methyl-2-benzylacrylate (20 gm, 0.113 mol) in methanol (100 ml) at room temperature was added a solution of sodium methoxide (2N, 17 ml) followed by isopropylthiol (12.56 ml). TLC (4:1, Hexanes: ethyl acetate) showed reaction to be complete after 30 min. The reaction mixture was made acidic with 1N HCl and extracted three times with ethyl acetate. The combined organic fractions were dried over NaSO4, filtered and evaporated in vacuo. The crude product was purified by chromatography (silica 4:1, hexanes: ethyl acetate to give methyl-3-isopropylthio-2-benzylpropionate.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:13].[CH3:14][N:15]([CH3:22])[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]([CH3:13])=[C:2]([N:19]2[CH2:20][CH2:21][CH:16]([N:15]([CH3:22])[CH3:14])[CH2:17][CH2:18]2)[CH:7]=1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: CN(C)C1CCNCC1
Product: COc1cc(N2CCC(N(C)C)CC2)c(C)cc1[N+](=O)[O-]

Procedure:
Starting Materials: 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (INTERMEDIATE 7) and N,N-dimethylpiperidin-4-amine. m/z 294.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][CH2:8][NH2:9].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26](Cl)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][CH2:8][NH:9][C:26](=[O:27])[CH2:25][C:19]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COc1ccc(OCCN)cc1OC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(=O)NCCOc2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.4 %

Procedure:
To a cold (0° C.) solution of 2-(3,4-dimethoxy-phenoxy)-ethylamine (2.3 g, 11.8 mmol) in anhydrous THF (21 ml), were added TEA (1.4 ml, 19.2 mmol) and portionwise 3,4-dimethoxyphenylacetylchloride (2.49 g, 11.6 mmol). The resulting mixture was stirred at RT for 20 h under nitrogen. The mixture was combined with H2O and extracted three times with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude solid. Recrystallisation from diethylether gave the title product (3.59 g, 80%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][C:4](=[O:9])[CH:3]=1.N[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH2:15][CH2:14]2.Cl>>[CH2:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:1][C:2]3[NH:7][C:6](=[S:8])[NH:5][C:4](=[O:9])[CH:3]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: Nc1cc(=O)[nH]c(=S)[nH]1
Agent: Cl
Product: O=c1cc(Nc2ccc3c(c2)CCC3)[nH]c(=S)[nH]1
Yield: 6 %

Procedure:
6-Amino-2-thiouracil is heated for 4 hours at 160° C. with an equimolar mixture of 5-aminoindan and the hydrochloride of 5-aminoindan. The product is crystallized from ethanol/water and isolated in 6% yield, mp 269°-272° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1>>[CH3:31][C:22]1[CH:27]=[CH:26][C:25]([C:28]([NH:21][C:18]2[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:16][CH:17]=2)=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Product: Cc1ccc(C(=O)Nc2ccc(OCc3c(-c4ccccc4)noc3C)nn2)cc1
Yield: 80 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) was converted, using p-toluoyl chloride instead of methoxyacetyl chloride, to the title compound (320 mg, 80%) which was obtained as a white solid. MS: m/e=401.3 [M+H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CO.C([BH3-])#N.[Zn+2].C([BH3-])#N>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Zn+2]
Solvent: CO
Product: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A suspension of 3-nitrobenzaldehyde (30 g, 0.2 mol) in methanol (150 ml) was treated with morpholine and the resulting orange solution cooled to 0° C. The solution of zinc cyanoborohydride prepared above was then introduced by means of a double-ended needle and the reaction stirred to ambient temperature over 16 hours. The reaction was filtered and the filtrate evaporated to dryness. The residue was dissolved in diethyl ether (600 ml) and washed with 1N hydrochloric acid (1 l). The organic layer (containing 3-nitrobenzyl alcohol) was discarded. The aqueous layer was made basic with 4N sodium hydroxide and extracted with diethyl ether (750 ml). The organic layer was dried over anhydrous sodium sulphate, filtered and pre-adsorbed on to silica. Purification by dry flash chromatography eluting with dichloromethane/methanol/0.880 NH3 (95:4.5:0.5) gave 4-(3-nitrobenzyl)morpholine as a pale yellow oil which crystallised on standing (22.2 g, 50%). δH (360 MHz, CDCl3) 2.45-2.48 (4H, m), 3.59 (2H, s), 3.71-3.74 (4H, m), 7.49 (1H, t, J 8), 7.68 (1H, d, J 8), 8.12 (1H, d, J 8), 8.22 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([OH:24])[CH3:23])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:26])([CH3:25])[NH:3]1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH3:23][CH:22]([O:24][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=1)(=[O:36])=[O:35])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]3[CH2:5][C:4]([CH3:26])([CH3:25])[NH:3][C:2]([CH3:1])([CH3:27])[CH2:7]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)Cc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1

Procedure:
The title compound was prepared from 1-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propan-2-ol and p-toluenesulfonyl chloride in pyridine. Yield: 177 mg (100%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:12]([CH:18]=1)[C:13]([O:15]CC)=[O:14])[CH2:4][CH2:5][CH3:6].C(O)C>O>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])=[C:12]([CH:18]=1)[C:13]([OH:15])=[O:14])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ccc(OCC(F)(F)F)c(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc(OCC(F)(F)F)c(C(=O)O)c1
Yield: 77.3 %

Procedure:
A solution of 2.5 g (0.062 mole) of sodium hydroxide in 60 ml of water was combined with 9.9 g (0.031 mole) of ethyl 5-butoxy-2-(2,2,2-trifluoroethoxy)benzoate and 50 ml of ethanol. The reaction mixture was heated at reflux for about sixteen hours then concentrated to remove most of the ethanol, diluted with water and acidified with 10% hydrochloric acid. The resulting solid was collected then recrystallized from a mixture of ethanol and water to provide 7.0 g of white crystalline 5-butoxy-2-(2,2,2-trifluoroethoxy)benzoic acid, m.p. 88.5°-90° C. Analysis: Calculated for C13H15F3O4 : %C, 53.4; %H. 5.2; Found: %C, 53.3; %H, 5.0.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:15](=[O:20])[N:16]([O:18][CH3:19])[CH3:17])[CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(C)(C)C.[ClH:22].O1CCOCC1>>[ClH:22].[NH2:7][C@@H:8]([CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:15]([N:16]([O:18][CH3:19])[CH3:17])=[O:20]
Reactant: CON(C)C(=O)[C@H](Cc1cccs1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CON(C)C(=O)[C@@H](N)Cc1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-[1-(Methoxy-methyl-carbamoyl)-2-thiophen-2-yl-ethyl]-carbamic acid tert-butyl ester (1.3 mmol) was dissolved in 4 M HCl-dioxane (1 mL) at 0° C. and the resulting solution stirred at 25° C. for 2 hours. The mixture was concentrated and the residue triturated with ether giving a yellow solid (321 mg, 96%; HPLC (60/40) 2.24 minutes (98%); MS 215 (MH+, 100%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].[H-].[Na+].Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[N:19]=1>CN(C=O)C>[CH3:9][C:3]([CH3:10])([CH2:4][S:5](=[O:7])(=[O:6])[NH2:8])[CH2:2][O:1][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[N:19]=1
Reactant: CC(C)(CO)CS(N)(=O)=O
Reactant: Clc1ccc2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(COc1ccc2nccn2n1)CS(N)(=O)=O
Temperature: 70 °C
Yield: 88 %

Procedure:
To a solution of 3.5 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide in 30 ml of DMF was added by portions 0.85 g of sodium hydride (60%, in oil) with stirring. To the mixture were added 3.18 g of 6-chloroimidazo[1,2-b]pyridazine and then 0.85 g of sodium hydride. The reaction solution was heated at 70° C. for 1.5 hours and then at 100° C. for an hour with stirring, and concentrated under reduced pressure. The residue was added into 100 ml of ice-water, extracted with ethyl acetate and tetrahydrofuran (1:1) (100 ml×4), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was recrystallized from ethanol to obtain 5.18 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][C:14]#[N:15])[N:8]=1.[NH3:19]>CO>[F:1][C:2]([F:18])([F:17])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][C:14]#[N:15])[N:8]=1
Reactant: N
Reactant: N#CCCn1ccc(NC(=S)NCC(F)(F)F)n1
Solvent: CO
Product: N#CCCn1ccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[3-(2,2,2-trifluoroethyl)-thioureido]-1-(2-cyanoethyl)pyrazole (2.8 g.), yellow mercuric oxide (4.0 g.), methanol (100 ml.) and saturated ethanolic ammonia solution (10 ml.) was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated to dryness and the residue partitioned between ether and water. The ether phase was dried and evaporated to give 3-[2-(2,2,2-trifluoroethyl)guanidino]-1-(2-cyanoethyl)pyrazole characterised as the hydrogen maleate, m.p. 141°-142° after recrystallisation from acetone.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:21][CH:22]1[O:25][CH:23]1[CH3:24]>>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]([CH2:24][CH:23]4[O:25][CH:22]4[CH3:21])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1ccccc13
Reactant: CC1OC1CBr
Product: Cc1ccc2c(=O)n3c4ccccc4n(CC4OC4C)c3nc2c1

Procedure:
3-Methyl-6-(2,3-epoxybutyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3-methylbenzimidazo[2,1-b]quinazolin-12(6H)one and 1-bromo-2,3-epoxybutane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O.FC(F)(F)[C:27](O)=[O:28]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH:27]=[O:28])[C:3]=1[OH:9]
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccc(F)cc1F
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Product: O=Cc1cc(F)cc(F)c1O
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
260 g (2.00 mol) of 2,4-difluorophenol are dissolved in 1.6 l of trifluoroacetic acid, and 560 g (4.00 mol) of hexamethylenetetramine are added in portions. After 30 min, the batch is warmed to 75° C. and stirred overnight. 2 l of 40 percent sulfuric acid are subsequently added at RT, the mixture is left to stir for 2.5 h, 1.5 l of ice-water are added, and the mixture is stirred for a further 30 min. The deposited precipitate is separated off, washed with water and taken up in dichloromethane. The resultant solution is dried over sodium sulfate and evaporated, giving 3,5-difluorosalicylaldehyde as a beige solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)[CH3:20]>>[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=3)=[CH:11][CH:12]=2)=[O:29])=[CH:23][CH:22]=1)[CH3:20]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: Nc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)cc1
Reaction time: 4.5 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(2-trifluoromethyl-pyridin-4-yloxy)-phenylamine (Example 108) and 4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 4.5 h. The title compound is obtained as a white solid: ES-MS: 401.9 [M+H]+; single peak at tR=9.33 min (System 2); Rf=0.37 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[NH:31][C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+].[C:42](OC(=O)C)(=[O:44])[CH3:43].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([C:42](=[O:44])[CH3:43])[C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1[C@H](C)CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a mixture of 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (150 mg, 0.3 mmol), potassium carbonate (84 mg, 0.6 mmol) in DMF (5 mL) was added acetic anhydride (0.3 mL) at −15° C. The mixture was slowly warmed to room temperature and stirred for 30 min. The reaction mixture was added 30 mL of water. The solid was collected to give 100 mg of 312. Yield=62%. 1H NMR (CDCl3, 400 MHz): δ8.03 (s, 1 H), 7.51-7.46 (m, 1H), 7.19-7.00 (m, 4H), 6.50 (d, J=8.8 Hz, 1 H), 4.19 (t, J=4.4 Hz, 2 H), 3.66-3.65 (m, 2 H), 3.07 (t, J=4.8 Hz, 2H), 0.93-2.89 (m, 2 H), 2.13 (s, 3 H), 2.03 (s, 2 H), 1.29-1.24 (m, 6 H). ESI-MS: m/z=537 [M+H+]
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+]=[N-].O.NN>[Ni].CO>[NH2:1][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)[C@@H](N=[N+]=[N-])C[C@@H]12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)[C@@H](N)C[C@@H]12

Procedure:
1.0 g 16β-azido-3-methoxy-estra-1,3,5(10)-triene-17α-ol, 10 ml methanol, 2 ml 80% hydrazine hydrate and a spatula tip of Raney nickel are heated on a water bath for 15 min. After filtration, the Raney nickel is washed with methanol, subsequently wash fluid and filtrate are combined and methanol is removed by distillation under vacuum. The residue is recrystallized from methanol/ether. Yield: 0.8 g (87%), F=158-160° C.; [α]D+68° (pyridine).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[N:27]1([C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]3[CH:7]=[CH:8][C:9]4[NH:10][C:36]([C:35]5[CH:34]=[CH:33][C:32]([N:27]6[CH2:31][CH2:30][CH2:29][CH2:28]6)=[CH:39][CH:38]=5)=[N:1][C:4]=4[CH:5]=3)=[O:26])=[CH:16][CH:17]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=Cc1ccc(N2CCCC2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCCC4)cc3)nc2c1)c1ccc(N2CCCC2)cc1

Procedure:
Compound 225 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-pyrrolidinylbenzaldehyde. [M+H]+ calcd for C28H29N5O: 452.25; found: 451.95.