Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([SH:22])[CH2:19][CH2:20][SH:21]>C(Cl)(Cl)Cl>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]3[S:22][CH2:18][CH2:19][CH2:20][S:21]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OCCN2CCCCC2)cc1
Reactant: SCCCS
Solvent: ClC(Cl)Cl
Product: c1cc(C2SCCCS2)ccc1OCCN1CCCCC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 67.7 %

Procedure:
A 500 mL, 3-neck round bottom flask was charged with 4-[2-(1-piperdinyl)ethoxy]benzaldehyde (2.3 g, 10.0 mmol) and 1,3-propanedithiol (1.2 mL, 1.1 g, 10.2 mmol) in 250 mL of anhydrous chloroform under a nitrogen atmosphere. The solution was cooled to near 0° C. and dry HBr gas was slowly bubbled through the reaction mixture for 8 minutes. The mixture was allowed to warm to ambient temperature while stirring during 3.5 hr. The reaction mixture was then added to a large excess of 1N NaOH and ice and the chloroform layer was separated. The chloroform solution was washed with two 50 mL portions of 1N NaOH solution and two 25 mL portions of brine and dried over anhydrous sodium sulfate. After filtration and removal of the chloroform solvent, the residue was triturated with 1:1 hexane:ethyl ether to provide 2.19 g (68%) of a crystalline product which was used without further purification.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:28]([NH:30][C@H:31]([C:39]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:40])[CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:38])[NH2:37])=[O:29])[CH2:22][O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH3:63][C:64]([OH:66])=[O:65].[CH3:67][C:68]([OH:70])=[O:69]>C(O)(=O)C>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:28]([NH:30][C@H:31]([C:39]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:40])[CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:37])[NH2:38])=[O:29])[CH2:22][O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9].[CH3:63][C:64]([OH:66])=[O:65].[CH3:67][C:68]([OH:70])=[O:69].[CH3:42][C:43]([OH:45])=[O:44]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
4.4 g of Z-Arg-Ile-Ser(tBu)-Arg-Pro-OtBu diacetate (crude substance) are dissolved in about 60 ml of 90% strength acetic acid and catalytically hydrogenated in analogy to Example 1b.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH2:15])[C:10]=1[CH2:11][CH3:12].[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH:15][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]=1[CH2:11][CH3:12]
Reactant: CCc1nn(CCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCc1nn(CCNC(=O)c2ccccc2)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
A solution of the amine of Example 43 (98 mg, 0.30 mmol) in dimethylformamide (3.75 ml) was treated with benzoic acid (41 mg, 0.33 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64 mg, 0.33 mmol) and 4-dimethylaminopyridine (81 mg, 0.66 mmol) and stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated sodium hydrogencarbonate solution. The organic extract was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) to afford the title compound (48 mg) as a white solid, m.p. 115–117° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:15][N:16](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:15]#[N:16])([CH3:14])([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1C#N
Temperature: 205 °C
Yield: 80 %

Procedure:
To a solution of 2-bromo-1-tert-butyl-4-nitrobenzene (2.13 g, 8.2 mmol) and Zn(CN)2 (770 mg, 6.56 mmol) in DMF (10 mL) was added Pd(PPh3)4 (474 mg, 0.41 mmol) under a nitrogen atmosphere. The mixture was heated in a sealed vessel at 205° C. for 5 h. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine and dried over MgSO4. After removal of solvent, the residue was purified by column chromatography (0-10% EtOAc-Hexane) to give 2-tert-butyl-5-nitrobenzonitrile (1.33 g, 80%). 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=2.3 Hz, 1H), 8.36 (dd, J=8.8, 2.2 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 1.60 (s, 9H); HPLC ret. time 3.42 min, 10-100% CH3CN, 5 min gradient.
Reaction SMILES: [NH2:1][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].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[C:25]([O:33][C:34]([F:37])([F:36])[F:35])[CH:24]=1>>[NH2:1][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)[N:4]([S:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][C:25]=2[O:33][C:34]([F:35])([F:36])[F:37])(=[O:31])=[O:30])[C:3]1=[O:12]
Reactant: COc1ccccc1C1(N)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1

Procedure:
With 5.54 g of 3-amino-5-chloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one 5.00 g, 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride, which is the compound described in Preparation 1.18A of the brochure Publication No. WO03/008407, as starting materials, 4.99 g of the title compound (light yellow solid) was obtained by a similar method to Example 2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14].[F:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=2[C:13]([F:15])([F:16])[F:14])=[CH:25][CH:24]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)c(C(F)(F)F)c1
Reactant: Oc1ccc(F)cc1
Product: N#Cc1ccc(N(CCOc2ccc(F)cc2)CC(F)(F)F)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-3-(trifluoromethyl)benzonitrile and 4-fluorophenol: MS (APCI) m/z 407 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)=[O:9].[NH2:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[CH:20][CH:21]=1>>[NH2:15][C:16]1[C:17]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)=[O:9])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccsc1
Product: Nc1cccnc1Nc1ccccc1C(=O)c1ccsc1

Procedure:
In accordance with the procedure of Intermediate 9, (2-aminophenyl)(3-thienyl)methanone is reacted with 3-amino-2-chloropyridine to give the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH:35]C=O)[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][CH:23]=[CH2:24])[CH:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl.CO>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][CH:23]=[CH2:24])[CH:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C=CCn1cnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=CCn1cnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 58.5 %

Procedure:
A mixture of 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.9 g), conc.hydrochloric acid (0.3 ml), methanol (7 ml) and tetrahydrofuran (7 ml) was stirred for 4.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 2.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-allyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.5 g).
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16].[C:18]([O-:21])(=[O:20])[CH3:19].[Na+].CN(C)C(=O)C>[I-].[Na+].O>[C:18]([O:21][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16])(=[O:20])[CH3:19]
Reactant: CC(=O)[O-]
Reactant: CC/C=C\C#CCCCCCCCCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC/C=C\C#CCCCCCCCCCCOC(C)=O
Temperature: 122.5 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer were placed Z-13-hexadecen-11-yn-yl chloride (254.8 g: 1.0 mol), sodium acetate (98.4 g: 1.2 mol), sodium iodide (8.9 g: 0.06 mol) and N,N-dimethylacetamide (113.2 g), and stirred at from 120 to 125° C. for 6 hours. After the completion of the reaction was confirmed by gas chromatography, water (350.0 g) was added to the reaction mixture. The organic phase separated from the aqueous phase was washed with an aqueous 1.0% by weight sodium bicarbonate solution (250.0 g). The organic phase was subjected to removal of the solvent under reduced pressure, followed by dehydration. The residue was then distilled under reduced pressure to obtain Z-13-hexadecen-11-yn-yl acetate [bp: from 126 to 130° C./0.13 KPa, 261.2 g, 0.94 mol]. [Yield: 93.8%]
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1([OH:33])[CH2:11][CH:10]2[C:12]([CH3:14])([CH3:13])[C:7]1([CH2:15][S:16]([N:19]1[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH2:21][CH2:20]1)(=[O:18])=[O:17])[CH2:8][CH2:9]2)C.[Na]>CO.O>[CH3:1][O:3][C:4](=[O:34])[CH2:5][C:6]1([OH:33])[CH2:11][CH:10]2[C:12]([CH3:14])([CH3:13])[C:7]1([CH2:15][S:16]([N:19]1[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH2:21][CH2:20]1)(=[O:17])=[O:18])[CH2:8][CH2:9]2
Reactant: CCOC(=O)CC1(O)CC2CCC1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C2(C)C
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)CC1(O)CC2CCC1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1S(1.Alpha.,2α,4α))-2-hydroxy-7,7-dimethyl-1-((spiro(1H-indene-1,4'-piperidin)-1'-yl sulfonyl)methyl)bicyclo(2.2.1)heptane-2-acetic acid ethyl ester (45 mg, 0.092 mmol) was stirred in a mixture of methanol (1 ml) and water (1 ml) and treated with sodium hxdroxide (0.1 ml of a 5N solution in water; 0.5 mmol). The mixture was stirred for 1 hr at ambient temperature, then evaporated to dryness in vacuo. The residue was treated with saturated sodium bicarbonate solution and extracted with ether. The ether layer was evaporated to dryness in vacuo and the residue was chromatographed on a silica gel column eluted with 15% EtOAc in hexane. The product fractions were evaporated to dryness in vacuo, and the residue was triturated with CH2Cl2 and again evaporated to dryness. The residue was dried in vacuo at ambient temperature overnight to give the title compound: (mp 81°-83°).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14](=O)([O:21]C1C=CC([N+]([O-])=O)=CC=1)[O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18]>ClCCCl>[N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][N:4]([C:14]([O:15][CH2:16][C:17]([NH:19][CH3:20])=[O:18])=[O:21])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CNC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Product: CNC(=O)COC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of 0.53 g (2.85 mmol) of 1,1-dimethylethyl 1-piperazinecarboxylate in 5 ml of 1,2-dichloroethane is added dropwise at about 0° C. to a solution, cooled to 0° C., of 1.1 g (3 mmol) of 2-(methylamino)-2-oxoethyl 4-nitrophenyl carbonate, prepared in step 2.2. of Example 2, in 10 ml of 1,2-dichloroethane. Stirring is continued at 0° C. for 1 hour, and then at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue thus obtained is purified by chromatography on silica gel, eluting with a 20/80 mixture of ethyl acetate and cyclohexane. The gradient is gradually increased to complete the elution with ethyl acetate. An oily residue that crystallizes from diisopropyl ether is obtained. 0.61 g of product is obtained in the form of a white solid, and is used without further purification in the following step.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-])=O)=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:3]=1[NH2:16]
Reactant: O=[N+]([O-])c1c(F)cccc1Nc1ccccc1F
Agent: [Pd]
Solvent: CO
Product: Nc1c(F)cccc1Nc1ccccc1F
Yield: 37.8 %

Procedure:
To 2-fluoroaniline (1.55 g, 13.9 mmol) in anhydrous dimethylformamide (10 mL) was added sodium hydride (0.56 g, 13.9 mmol) and the reaction stirred for 10 minutes prior to the addition of 2,6-difluoronitrobenzene (2 g, 15.5 mmol) dissolved in anhydrous dimethylformamide (2 mL). Upon disappearance of 2-fluoroaniline the reaction was partitioned between saturated ammonium chloride (50 mL) and ethyl acetate (50 mL) and the organics were dried over sodium sulfate. The product was purified on silica gel using the ISCO (0-70% ethyl acetate/hexane) to give (3-Fluoro-2-nitro-phenyl)-(2-fluoro-phenyl)-amine as a slightly impure off-white solid (1.5 g, 43%). (3-Fluoro-2-nitro-phenyl)-(2-fluoro-phenyl)-amine (1.5 g, 6 mmol) and a spatula tip of 5% Pd/C in methanol (100 mL) were reduced in the parr shaker. Upon complete reduction, the reaction was filtered through a pad of celite and concentrated onto silica gel. The product was purified on silica gel using the ISCO (0-70% ethyl acetate/hexane) to give 3-fluoro-N1-(2-fluorophenyl)benzene-1,2-diamine as a brown oil (0.5 g, 38%). MS (ES) m/z 221.1
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C([Li])CCC.CN(C)[CH:18]=[O:19]>O1CCCC1>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([CH:18]=[O:19])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromoindazole (5 g, 25.38 mmol) in tetrahydrofuran (100 mL) cooled at −50° C. under argon was added dropwise a solution of 1.6 M n-butyllithium in hexanes (40 mL, 63.44 mmol). Dimethylformamide (3.9 mL, 50.75 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 15 minutes. The mixture was then quenched with water, extracted with ethyl acetate, preabsorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10-30% ethyl acetate in hexanes to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.03 (s, 1H) 8.45 (s, 1H) 8.35 (s, 1H) 7.85 (dd, J=8.70, 1.37 Hz, 1H) 7.69 (d, J=8.54 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:2][C:3]2[S:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: BrCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(OCc2cccs2)cc1

Procedure:
To a solution of 51.75 g (0.29 m) of 2-bromomethylthiophene and 38.6 g (0.3 m) of 4-chlorophenol in 400 ml of acetonitrile was added, all at once, 38.6 g of powdered potassium carbonate. The resulting mixture was stirred and heated at reflux for one (1) hour. The solvent was removed by evaporation under reduced pressure and 400 ml of water was added to the residue. The resulting aqueous mixture was extracted three times with 200 ml portions of ether. The organic extracts were combined and then washed sequentially with 50 ml of a 10 percent sodium hydroxide solution, 300 ml of water and 300 ml of a saturated sodium chloride solution. The extracts were dried over magnesium sulfate and the solvent removed by evaporation under reduced pressure. The residue was an orange oil which slowly solidified upon standing. Distillation of the residue gave a main fraction boiling at 96°-100° C. at 0.01 millimeter of mercury. The crude product slowly crystallized and was purified by recrystallization from hexane. The (4-chlorophenoxy)methylthiopene product, a white solid, was recovered in a yield of 41 g (63 percent of theoretical) and melted at 45°-47° C.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[C:5]12([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[N:19][C:18]=3Cl)[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC.CCOC(C)=O>[C:5]12([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[N:19][C:18]=3[S:4][CH2:1][CH2:2][CH3:3])[CH2:6][CH:7]3[CH2:8][CH:9]([CH2:10][CH:11]([CH2:13]3)[CH2:12]1)[CH2:14]2
Reactant: CCCS
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCC#N
Product: CCCSc1nc(Cl)ccc1C(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 150 °C
Yield: 121.1 %

Procedure:
1-Propanethiol (0.499 mL, 5.50 mmol) was added dropwise to N-adamantan-1-yl-2,6-dichloronicotinamide (1.63 g, 5 mmol) and potassium carbonate (2.07 g, 15.00 mmol) in butyronitrile (15 mL) at 20° C. over a period of 2 minutes under nitrogen. The resulting suspension was heated at 150° C. for 2 hours. The reaction mixture was diluted with EtOAc (60 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford N-adamantan-1-yl-6-chloro-2-(propylthio)nicotinamide (2.21 g, 100%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:14])[CH2:10][CH2:11][CH2:12]Cl.[OH-].[Na+]>C(Cl)Cl.C(Cl)CCl.[Cl-].C[N+](CCCC)(CCCC)CCCC>[CH:10]1([C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH2:2])=[O:14])[CH2:12][CH2:11]1
Reactant: Nc1ccccc1C(=O)CCCCl
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Product: Nc1ccccc1C(=O)C1CC1
Temperature: 50 °C
Yield: 66.8 %

Procedure:
A solution of 0.30 g (1.3 mmol) of 1-(o-aminophenyl)-4-chloro-1-butanone hydrochloride in 3 mL of methylene chloride and 3 mL of ethylene dichloride is treated with 1.2 g (3 mmol) of 10% sodium hydroxide solution and 0.05 g (0.2 mmol) of 75% aqueous methyl tributylammonium chloride and heated to 50° C. for about 5 hours. After cooling to room temperature, the phases are separated. The aqueous layer is extracted with methylene chloride. The combined organic extracts are washed with water and concentrated in vacuo to give 0.14 g (70% yield) of o-aminophenyl cyclopropyl ketone (mp 46-48° C.). The product is identified by NMR and MS analyses.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:16])[CH:13]=2)[C:8]1([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)O)[CH3:5]>>[ClH:1].[F:16][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:7]([CH2:6][N:4]([CH3:5])[CH3:3])[CH2:15]2)=[CH:10][CH:11]=1
Reactant: CN(C)CC1Cc2cc(F)ccc2C1(O)c1cccnc1
Agent: Cl
Product: CN(C)CC1=C(c2cccnc2)c2ccc(F)cc2C1
Reaction time: 8 h

Procedure:
About 5.4 ml of 37% hydrochloric acid were added at room temperature to 0.5 g of 2-dimethylaminomethyl-5-fluoro-1-pyridin-3-yl-indan-1-ol hydrochloride (mixture of the diastereoisomers); stirring was carried out overnight, followed by concentration in vacuo. The residue was taken up twice in dichloromethane and concentrated again. The residue was taken up in 15 ml of acetone and stirred for 2 hours, whereupon a crystalline solid formed, which was filtered off with suction, with the exclusion of air, washed twice with diethyl ether and dried at 60° C. under an oil-pump vacuum. 0.39 g of (6-fluoro-3-pyridin-3-yl-1H-inden-2-ylmethyl)-dimethyl-amine hydrochloride was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](C(OC(C)(C)C)=O)[CH:7]=[C:6]2/[C:19](/[C:27]#[CH:28])=[CH:20]/[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+].C[O-].[Na+].C(OCC)C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2/[C:19](/[C:27]#[CH:28])=[CH:20]/[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: C#C/C(=C\c1cccnc1)c1cn(C(=O)OC(C)(C)C)c2ccc(OC)cc12
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: C#C/C(=C\c1cccnc1)c1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of (E)-tert-butyl 5-methoxy-3-(1-(pyridin-3-yl)but-1-en-3-yn-2-yl)-1H-indole-1-carboxylate (270 mg, 0.72 mmol, 1.0 eq.) in ethanol (40 mL) were added K2CO3 (1.2 g, 8.6 mmol, 12.0 eq.) and sodium methanolate (232 mg, 4.3 mmol, 6.0 eq.), and then, the reaction was stirred at room temperature for 3 days. The solvent was removed and the residue taken up in ethyl acetate. The organic layer washed with water, dried over MgSO4, filtered through a silica gel pad and then, evaporated under reduced pressure to afford, after trituration with diethyl ether, the compound (58) as a yellowish powder (180 mg, 91%). mp: 136° C.; IR νmax (cm−1): 2089 (νCC alcyne); 1H RMN (DMSO, 300 MHz) δ (ppm): 3.81 (3H, s, 5-methoxy), 4.64 (1H, s, H4′), 6.84 (1H, dd, J6-7=8.9 Hz, J6-4=2.3 Hz, H6), 7.29 (1H, s, H1′), 7.35 (1H, d, J7-6=8.9 Hz, H7), 7.42 (1H, dd, J5″-4′=7.3 Hz, J5″-6″=4.5 Hz, H5″), 7.49 (1H, d, J4-6=2.3 Hz, H4), 7.67 (1H, s, H2), 8.46 (2H, m, H4″ and H6″), 9.03 (1H, s, H2″), 11.37 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 55.4 (5-methoxy), 82.5 (C3′), 86.7 (C4′), 102.2 (C4), 111.7 (C6), 112.8 (C7), 114.2 (C2′), 117.7 (C3), 123.2 (C5″), 124.4 (C3a), 126.4 (C1′), 127.0 (C2), 132.2 (C7a), 132.7 (C3″), 134.3 (C4″), 147.9 (C6″), 149.8 (C2″), 154.0 (C5); ESI-MS: m/z 275.1 ([M+H]+); HRESI-MS: m/z 275.1176 (calcd for C18H15N2O+, 275.1184).