Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[NH2:8][CH2:9][CH2:10][NH2:11]>C(O)C>[O:6]=[S:1]1(=[O:7])[CH2:5][CH2:4][CH:3]([NH:8][CH2:9][CH2:10][NH:11][CH:3]2[CH2:4][CH2:5][S:1](=[O:7])(=[O:6])[CH2:2]2)[CH2:2]1
Reactant: NCCN
Reactant: O=S1(=O)C=CCC1
Solvent: CCO
Product: O=S1(=O)CCC(NCCNC2CCS(=O)(=O)C2)C1

Procedure:
To a 500 ml. round bottom flask equipped with condenser, thermometer and a stirrer were introduced 118 g. (1.0 mole) of 4,5-dihydrothiophene 1,1-dioxide, 200 ml. of 70% by weight aqueous ethanol and 30 g. (0.5 mole) of 1,2-diaminoethane (ethylenediamine). The reaction mixture was heated at reflux (80°-85°C) for 4 hours. The solvent was then removed under a reduced pressure. The product, N,N'-bis(1,1-dioxotetrahydro-3-thienyl)-1,2-diaminoethane, obtained was a viscous liquid that became a solid, m.p. 60°-85°C. IR spectrum showed absorptions at 3300 cm-1 (NH), at 1300 cm-1 and 1140 cm-1 (SO2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21](=[O:24])[CH2:22]Br.O>CN(C)C=O>[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21](=[O:24])[CH2:22][N:10]1[C:11]([CH3:13])=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1
Reactant: Cc1cc(-c2ccc(Cl)cc2)n[nH]1
Reactant: COC(=O)CCC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCC(=O)Cn1nc(-c2ccc(Cl)cc2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
3-(4-Chloro-phenyl)-5-methyl-1H-pyrazole (1.84 g, 9.6 mmol) was dissolved in dimethylformamide (20 ml) followed by the addition of sodium hydride (60% dispersion in oil, 384 mg, 9.6 mmol). The reaction was stirred at room temperature for 15 min, followed by the addition of 5-bromo-4-oxo-pentanoic acid methyl ester (2 g, 9.6 mmol). The reaction was stirred at room temperature for a further 30 min, before the addition of water (200 ml). The solution was then extracted with ethyl acetate (2×150 ml). The organics were dried over magnesium sulfate and concentrated in vacuo. The crude product was then purified by column chromatography (120g column, DCM to 90% DCM/EtOAc over 50 mins) to give 5-[3-(4-chloro-phenyl)-5-methyl-pyrazol-1-yl]-4-oxo-pentanoic acid methyl ester (1.84 g).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:19]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]3[CH:30]=[C:31]([Cl:35])[C:32]([NH2:34])=[CH:33][C:21]=3[N:20]=2)[CH:18]=1)=[O:13])[CH3:10].NC1C(Cl)=CC2NC(N3C=C(C(O)=O)C=N3)=NC=2C=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:19]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]3[CH:30]=[C:31]([Cl:35])[C:32]([N:34]=[CH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:33][C:21]=3[N:20]=2)[CH:18]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2nc3cc(N=Cc4ccccc4)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 78.4 %

Procedure:
Benzaldehyde (93.0 mg, 0.876 mmol), 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.300 g, 0.762 mmol), THF (3 mL), and 4 Å molecular sieves (0.910 g) were combined and stirred for 18 h at 23° C. Sodium triacetoxyborohydride (0.242 g, 1.14 mmol) was added and stirring was continued for 4 days. The reaction was quenched with saturated aqueous sodium bicarbonate (15 mL) and stirred with dichloromethane (25 mL). This mixture was filtered and the layers were separated. The aqueous layer was extracted with dichlormethane (2×25 mL) and the combined organic layers were washed with brine (20 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-45% EtOAc/hexanes) to yield the titled compound (0.288 g, 78% yield) as a 4:3 mixture of regioisomers. The titled compound was not stable enough to obtain a mass spectrum. 1H NMR (400 MHz, CDCl3): 8.87 (s, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 8.03-7.94 (m, 2H), 7.73 (s, 1H), 7.58-7.48 (m, 3H), 7.39 (s, 1H), 6.12 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.7-3.6 (m, 2H), 3.5-3.4 (m, 2H), 3.32 (s, 3H), 1.39 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[S:13][C:6]2[NH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1)=O.Cl.[NH2:15]O>>[C:1]([C:3]1[S:13][C:6]2[NH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1)#[N:15]
Reactant: O=Cc1cc2cc(C(=O)O)[nH]c2s1
Reactant: NO
Agent: Cl
Product: N#Cc1cc2cc(C(=O)O)[nH]c2s1

Procedure:
2-Formyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Soth, S. et al., Bull. Soc. Chim. Fr., 2511-2515 (1975)) was treated with hydroxylamine hydrochloride according to Procedure G (100° C. for 13 h, 125° C. for 7 h; after cooling to room temperature, concentration gave crude product).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:16][CH2:17][C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:30][C:31]1[CH:32]=[C:33]([O:38][S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH:34]=[CH:35][C:36]=1[Cl:37]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:16][CH2:17][C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:30][C:31]1[CH:32]=[C:33]([O:38][S:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)(=[O:40])=[O:41])[CH:34]=[CH:35][C:36]=1[Cl:37])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=S(=O)(Oc1ccc(Cl)c(CBr)c1)c1ccccc1
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1CCc1ccsc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCc3cc(OS(=O)(=O)c4ccccc4)ccc3Cl)ccc2n1CCc1ccsc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-hydroxy-1-[(2-thiophen-3-yl)ethyl]-1H-indole-2-carboxylic acid ethyl ester (0.42 g, 1.33 mmol) in dry DMF (10 mL) was added Cs2CO3 (0.65 g, 1.99 mmol). After stirring at 60° C. for 30 min, benzenesulfonic acid 3-bromomethyl-4-chlorophenyl ester (0.48 g, 1.33 mmol), from Example 1(b) above, was added. The reaction was kept stirring at 60° C. for 18 h. The reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacua. Purification by flash column chromatography (silica gel, EtOAc/hexanes) afforded the partially purified product which was used directly in the next step without further purification (see Examples 1(h) and 2(c)).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].CS(O[CH:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[C:29]([O:28][C:26]([N:24]1[CH2:25][CH:22]([O:1][C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:23]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
100 mg (0.38 mmol) of the compound of Example 24A and 104 mg (0.42 mmol) of tert-butyl 3-[(methylsulphonyl)oxy]azetidine-1-carboxylate together with 259 mg (0.80 mmol) of caesium carbonate were initially charged in 1 ml of DMF and stirred at 90° C. overnight. The mixture was then stirred into 10 ml of 0.1 M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 18). This gave 60 mg (88% pure, 33% of theory) of the title compound.
Reaction SMILES: [C:1]1([C:7]2(N(C)CCCCCCC)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>C(OCC)(=O)C>[CH3:23][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:33]([CH2:25][CH2:24][CH2:29][CH2:28][CH2:27][CH2:26][CH3:30])[CH2:34][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:22]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCN(C)C1(c2ccccc2)CCCC1
Solvent: CCOC(C)=O
Product: CCCCCCCN(CC1(c2ccccc2)CCCC1)C(=O)Nc1c(C(C)C)cccc1C(C)C
Yield: 109.2 %

Procedure:
1-Phenylcyclopentyl-N-heptylmethylamine (5.46 g; 0.02M) was dissolved in 75 mL of ethyl acetate. To this solution was added, with stirring, a solution of 2,6-diisopropyl phenyl isocyanate (4.06 g; 0.02M) in 25 mL of ethyl acetate. The reaction mixture was stirred at room temperature overnight, concentrated to dryness, and the resulting white solid was chromatographed on silica using hexane:ethyl acetate (8:2) as the eluant to yield 5.2 g of the title compound, mp 95-97° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.O.O=[CH:11][C:12]([OH:14])=[O:13].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(#N)C>[N:15]1([CH:11]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:12]([OH:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OB(O)c1ccsc1
Reactant: C1CCNCC1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC#N
Product: O=C(O)C(c1ccsc1)N1CCCCC1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Thiophen-3-ylboronic acid (300 mg, 2.34 mmol) was added to a solution of 2-oxoacetic acid hydrate (216 mg, 2.34 mmol) and piperidine (0.23 ml, 2.34 mmol) in acetonitrile (11.7 ml). The mixture was heated to reflux for 5 hours. The reaction was cooled to room temperature and the suspension was filtered on a buckner funnel washing with acetonitrile (8 ml). The title compound (528 mg, quantitative yield) was collected from the filter as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:15](=O)[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:13][S:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[CH2:30]([NH:33][NH2:34])[CH2:31][CH3:32]>CO>[CH2:30]([N:33]1[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:29])([F:28])[F:1])[CH:4]=2)[CH:10]2[CH2:11][S:12][CH2:13][C:14](=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:15]2=[N:34]1)[CH2:31][CH3:32]
Reactant: O=C1C(=Cc2cccc(C(F)(F)F)c2)CSCC1=Cc1cccc(C(F)(F)F)c1
Reactant: CCCNN
Solvent: CO
Product: CCCN1N=C2C(=Cc3cccc(C(F)(F)F)c3)CSCC2C1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 26.9 %

Procedure:
A mixture of 4.28g of tetrahydro-3,5-bis-[[3-(trifluoromethyl)phenyl]methylene]-4H-thiopyran-4-one and 962mg of n-propyl hydrazine in 150ml of methanol is heated at reflux temperature for 3 hours and then cooled to room temperature. Solids are collected and washed to give 1.3g of the title compound, melting point 90°-93.5°C. The combined mother liquor and washings are concentrated to 100ml and 15-20ml of water is added to the hot solution. Upon cooling, an additional 1.8g of material is collected and recrystallized from methanol/water to give 1.6g of the title compound, melting point 89°-93°C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][CH2:7][C:8](=O)[CH2:9][CH3:10].[C-]#N.[K+].CC(N1CCCC1)(C)[C:17]#[N:18]>O>[CH2:7]([C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH2:9][CH3:10])[C:17]#[N:18])[CH3:6]
Reactant: CC(C)(C#N)N1CCCC1
Reactant: C1CCNC1
Reactant: CCC(=O)CC
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CCC(C#N)(CC)N1CCCC1
Yield: 100 %

Procedure:
The title compound (8.8 g, 100%) was prepared from pyrrolidine (8.96 ml, 0.107 mol), 3-pentanone (8.61 g, 0.1 mol) and potassium cyanide (6.51 g, 0.1 mol) in water (50 ml) in a similar manner to that described in D4. 1H NMR (CDCl3) δ: 0.95 (6H, t, J=7.6 Hz), 1.67-1.90 (8H, m), 2.67-2.72 (4H, m).
Reaction SMILES: [CH:1]([C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([OH:13])[O:5]1)([CH3:3])[CH3:2].[CH2:14]([Mg]Cl)[CH:15]([CH3:17])[CH3:16].C(Cl)C(C)C.[Mg]>C1COCC1>[OH:5][C@H:4]([C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@@H:6]([OH:13])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)C[Mg]Cl
Reactant: CC(C)[C@@H]1OC(O)c2ccccc21
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(C)CCl
Product: CC(C)C[C@H](O)c1ccccc1[C@@H](O)C(C)C

Procedure:
To a solution of (3S)-3-isopropyl-1,3-dihydro-isobenzofuran-1-ol (14.11 g, 0.129 mol) in THF (250 ml) was added at reflux temperature through a Teflon tube, which ended under the surface in the reaction mixture, a solution of isobutyl magnesium chloride (freshly prepared from 0.387 mol isobutyl chloride and 0.58 mol magnesium in 250 ml of THF) slowly within 20 minutes under efficient stirring. The mixture was then quenched with a solution of ammonium chloride (10%). The organic layer was separated, and the solvent was removed on the rotavapor. The residue was re-dissolved in ethyl acetate (200 ml), and this solution was washed with water (150 ml) and brine (150 ml). After drying and removal of the solvent the product was obtained as a yellow oil (31.5 g). 1H/13C-NMR (300 MHz, CDCl3, HSQC/HMBC) δ/δ 0.78 (d, J=6.9 Hz)/19.00, 1.04 (d, J=6.5 Hz)/20.22 (2 i-Pr CH3); 0.95 (d, J=6.5 Hz)/23.87, 0.96 (d, J=6.5 Hz)/22.32 (2 i-Bu CH3); 1.80 (m)/25.33 (i-Bu CHMe2); 2.02 (m)/35.13 ((i-Pr CHMe2); 1.47/1.72 (m)/48.03 (CH2); 3.09 (br s, 2 OH); 4.53 (d, J=8.1 Hz)/77.55 (CH(OH)i-Pr); 5.08 (dd, J=4.7 Hz, J=9.5 Hz)/68.87 (CH(OH)i-Bu); 7.40 (m)/126.44 (Ar i-Bu ortho-CH); 7.21 (m)/127.37 (Ar meta-CH); 7.28 (m)/127.55 (Ar i-Pr ortho-CH); 7.23 (m)/127.71 (Ar meta-CH); 140.56 (Ar i-Pr ipso-C); 142.66 (Ar i-Bu ipso-CH).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH3:23])[CH2:18][CH2:17]1)=O.P(Cl)(Cl)(Cl)(Cl)Cl>P(Cl)(Cl)(Cl)=O>[CH3:23][N:19]1[CH2:20][CH2:21][CH2:22][N:16]([C:14]2[N:3]3[CH:4]=[CH:5][N:1]=[C:2]3[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:13]=2)[CH2:17][CH2:18]1
Reactant: CN1CCCN(C(=O)Nc2ccccc2Cc2ncc[nH]2)CC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCCN(C2=Nc3ccccc3Cc3nccn32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 2.46 g of 1-[2-(2-imidazolylmethyl)phenylcarbamoyl]-4-methylhomopiperazine in 19.4 ml of phosphorus oxychloride is added at once 1.66 g of phosphorous pentachloride and the mixture is stirred at room temperature for 4 hours. The mixture is evaporated to dryness, the residue is suspended in 45.2 ml of methylene chloride, the suspension is cooled to 0° and 21.4 ml of triethylamine are added dropwise with stirring over a period of 15 minutes. The mixture is allowed to warm up to room temperature, stirred for 1.5 hours and poured into 10% aqueous potassium carbonate. The methylene chloride layer is separated, the aqueous layer is washed with methylene chloride and the combined methylene chloride extracts are dried over MgSO4, decolorized with charcoal and evaporated to dryness. The residue is purified by column chromatography with 50 g of silica gel, using methylene chloride-methanol-conc. ammonium hydroxide (300:50:1) as eluent to give 5-(4-methyl-1-homopiperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine as an oil. This free base is dissolved in acetone and treated with maleic acid to give 5-(4-methyl-1-homopiperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine monomaleate, m.p. 160°-163°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.[CH3:14][CH:15]([C:24](=O)[CH3:25])[CH2:16][CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:22])=[O:21]>C(O)(=O)C>[F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:10]=[C:24]([CH3:25])[C:15]2([CH3:14])[CH2:16][CH2:17][CH2:18][CH2:19][S:20]([OH:23])(=[O:21])=[O:22]
Reactant: CC(=O)C(C)CCCCS(=O)(=O)O
Reactant: NNc1ccc(SC(F)(F)F)cc1
Solvent: CC(=O)O
Product: CC1=Nc2ccc(SC(F)(F)F)cc2C1(C)CCCCS(=O)(=O)O
Yield: 14.2 %

Procedure:
To 4-(trifluoromethylthio)phenylhydrazine (1 g) in acetic acid (40 ml) was added 5-methyl-6-oxoheptane-1-sulphonic acid (1.4 g) and the solution heated to reflux overnight. The volatiles were removed on a rotary evaporator to give the crude product, 1.1 g of which was purified by preparative HPLC. The relevant fractions were combined, concentrated on a rotary evaporator and freeze dried to give the desired product (260 mg). M+=381
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]1([S:12]([N:15]2[CH:26]=[CH:25][C:24]3[C:16]2=[N:17][CH:18]=[C:19]2[C:23]=3[N:22]([C@H:27]3[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]3)[N:21]=[N:20]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:5][O:4][C:2](=[O:3])[NH:32][C@H:29]1[CH2:30][CH2:31][C@H:27]([N:22]2[C:23]3[C:19](=[CH:18][N:17]=[C:16]4[C:24]=3[CH:25]=[CH:26][N:15]4[S:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:14])=[O:13])[N:20]=[N:21]2)[CH2:28]1
Reactant: COC(=O)Cl
Reactant: N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Reaction time: 4 h
Yield: 99.5 %

Procedure:
Methyl chloroformate (31.0 μL, 0.40 mmol) was added to a stirred mixture of racemic trans 3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentylamine (150 mg, 390 μmol) and diisopropylethylamine (135 μL, 790 μmol) in DCM (3 mL) at ambient temperature. Stirring was continued for 4 hours. The mixture was concentrated under vacuum and the residue obtained purified by column chromatography on silica gel (gradient: 0 to 100% ethyl acetate in pentane) to afford 171 mg (98%) of racemic trans [3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-carbamic acid methyl ester as a colourless foam. LCMS (Method B, ESI): RT=3.48 min, m+H=441.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:11]3[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:31])[C:27]=1[C:28](O)=[O:29])=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:31])[C:27]=1[C:28](=[O:29])[NH:16][C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:17]=[C:11]2[CH:12]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Yield: 57.8 %

Procedure:
The product was prepared in the same manner as described in example 28 using 2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (580 mg, 2.54 mmol) and 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (604 mg, 3.05 mmol) as starting materials. The reaction affords 5-[2-(3-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (600 mg, 57.8%) as white solid. mp.: 246-249° C., MS: m/z=409.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([CH:13]([CH3:16])[CH2:14]O)[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22].S(Cl)([Cl:25])=O>C(Cl)(Cl)Cl>[Cl:25][CH2:14][CH:13]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=2)[C:5](=[O:22])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]1)[CH3:16]
Reactant: CCOC(=O)c1cn(C(C)CO)c2cc(F)c(F)cc2c1=O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C(C)CCl)c2cc(F)c(F)cc2c1=O

Procedure:
4.45 gm (14.3 mmol) of ethyl 6,7-difluoro-1,4-dihydro-1-(1-hydroxyprop-2-yl)-4-oxoquinoline-3-carboxylate and 5.10 gm (42.9 mmol) of thionyl chloride were dissolved into 130 ml of chloroform for reaction with heating under refluxing for 1 hour. After cooling, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=100:1), and recrystallized from ethanol to obtain 3.53 gm of colorless, needlelike crystals of ethyl 1-(1-chloroprop-2-yl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate:
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#N)(=[O:5])C.[CH3:14]O>>[CH2:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[C:3]([OH:5])=[O:1])[CH3:14]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: CCc1cccc(C(=O)O)c1
Temperature: 90 °C

Procedure:
6M Sodium hydroxide (25 mL) was added to 3-acetylbenzonitrile (850 mg, 5.82 mmol) in methanol (25 mL) and then heated at 90° C. overnight. After concentrating the reaction mixture, the aqueous layer was washed with dichloromethane (2×), then acidified pH˜3 with 12M HCl. The precipitate was extracted with ethyl acetate then washed with water and saturated brine, dried over anhydrous sodium sulfate filtered and concentrated to afford 3-ethylbenzoic acid as a colorless oil; 0.800 g (92%). 1H NMR (CDCl3) δ (ppm): 8.70 (s, 2H), 8.33 (d, 2H), 8.24 (d, 2H), 7.64 (t, 1H), 2.70 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]#[C:10][C:11]2[C:12]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=2)=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O>C(Cl)Cl>[CH:20]1([NH:19][C:12]2[C:11]([C:10]#[C:9][CH2:8][O:7][C:6]3[CH:26]=[CH:27][C:3]([CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[CH:4][CH:5]=3)=[CH:16][N:15]=[C:14]([C:17]#[N:18])[N:13]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: N#Cc1ncc(C#CCOc2ccc(CCl)cc2)c(NC2CCCCC2)n1
Solvent: ClCCl
Solvent: O
Product: CN1CCN(Cc2ccc(OCC#Cc3cnc(C#N)nc3NC3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
5-[3-(4-Chloromethyl-phenoxy)-prop-1-ynyl]-4-cyclohexylamino-pyrimidine-2-carbonitrile (0.050 mmol) is dissolved in CH2Cl2 (2 ml) and 1-methyl-piperazine (0.10 mmol) is added at room temperature and the mixture is stirred at room temperature for overnight. Water is added and the organic layer is washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give the product in 40% yield.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH3:25])[CH:19]=1)=O>CC(C)=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)=[CH:19][C:20]=1[CH3:25]
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: Cc1cc(C(=O)CBr)ccc1Cl
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccc(Cl)c(C)c3)cs2)c(C)s1
Yield: 70.5 %

Procedure:
155 mg (0.627 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 10 mL of reagent grade acetone. 2-Bromo-1-(4-chloro-3-methylphenyl)ethan-1-one (0.658 mmol; 163 mg) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and the reaction mixture was concentrated and dissolved in 50 mL of CH2Cl2. The organic layer was washed with 50 mL of 1N HCl (aq.), dried over sodium sulfate and concentrated. The crude product was purified on a 1 mm silica plate eluting with 20% ethyl acetate/hexane to afford 168 mg (68% yield) of methyl 4-[4-(4-chloro-3-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.