Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[NH:2][CH:3]=[CH:4][C:5]2[C:9]=1[C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=2.[H][H]>[Pd].CO>[CH2:1]1[C:9]2[C:5]([CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH2:3][NH:2]1
Reactant: COC(=O)c1ccc2cc[nH]cc1-2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1=C2CNCC=C2C=C1
Yield: 53.1 %

Procedure:
A hydrogenation bottle is charged with 2-pyrindine-7-carboxylic acid, methyl ester (0.8 g, 4.57 mmol), 5% Pd on carbon (2.0 g, wet) and methanol (125 ml). The slurry is hydrogenated (40 psi) until hydrogen uptake stops. The reaction mixture is filtered through celite and then evaporated to dryness to provide the product (430 mg) in 53% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH:10]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:9]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCc1ccc(C(CCCC(=O)O)c2cccnc2)cc1
Product: O=C(O)CCCC(c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)c1cccnc1

Procedure:
Prepared analogously to Example 10e from 5-(4-(2-aminoethyl)phenyl)-5-(3-pyridyl)pentanoic acid and 4-chlorobenzenesulphonic acid chloride.
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:13][C:14]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:15]=1[C:16](O)=[O:17]>>[Cl:13][C:14]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:15]=1[C:16]([NH:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[O:17]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCC12CC3CC(CC(C3)C1)C2
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc([N+](=O)[O-])ccc1Cl
Yield: 80.5 %

Procedure:
Prepared according to the method of Example 14 from 1-adamantanemethylamine (1.0 g) and 2-chloro-5-nitrobenzoic acid (1.22 g) to give the title compound as a yellow solid (1.7 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:31])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[CH:21][CH:22]=1)=[O:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:15]([NH:14][CH2:13][CH:12]([OH:31])[CH2:11][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)carbamoyl)phenyl)carbamate (500 mg, 1.18 mmol) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated, and the residue was dissolved in water, the pH was adjusted to 7˜7.5 with saturated aqueous of NaHCO3 and extracted with EA. The organic layer was concentrated to give the title product that was used in the next step without further purification (450 mg). LCMS (m/z): 326.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1([CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[CH:12][CH:13]=[N:14]3)=[CH:9][C:8]=2[O:41][CH3:42])[CH2:4][CH2:3]1.[O:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1.CC(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:40][C:19]1[CH:20]=[C:21]([N:24]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:11]1[C:10]2[C:15](=[CH:16][C:7]([O:6][CH2:5][C:2]3([NH:1][CH:46]4[CH2:47][CH2:48][O:43][CH2:44][CH2:45]4)[CH2:3][CH2:4]3)=[C:8]([O:41][CH3:42])[CH:9]=2)[N:14]=[CH:13][CH:12]=1
Reactant: O=C1CCOCC1
Reactant: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCC1(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCC1(NC2CCOCC2)CC1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
The product of Example 2 (200 mg) was mixed with tetrahydro-4H-pyran-4-one (45 mg), NaHB(OAc)3 (96 mg) and HOAc (42 mg) in DCM (5 ml). The reaction mixture was stirred at 30° C. overnight. Saturated NaHCO3 (20 ml) was added to the reaction and the solution was further extracted with EtOAc twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated and purified by preparative TLC plate to give the titled compound. Mass: (M+1), 659
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.CCCCCC.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12
Reactant: N#Cc1cnc2c(sc3ccccc32)c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: N#Cc1cnc2c(sc3ccccc32)c1Cl
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 1.01 g (4.47 mmol) of 4-hydroxybenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 7 mL of phosphorous oxychloride is heated at reflux temperature for 40 minutes, then cooled to room temperature. Hexane is added and the solid is collected by filtration, dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to a small volume. The solids are collected by filtration to give 696 mg (64%) of product, mp 305–308° C.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)[CH2:3][OH:4].N1C=CN=C1.[CH3:27][C:28]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CN(C=O)C>[Si:31]([O:4][CH2:3][CH:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[CH:9][CH:10]=1)[OH:1])([C:28]([CH3:30])([CH3:29])[CH3:27])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(Nc1cccc(C(O)CO)c1)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(O)c1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 53.7 %

Procedure:
Benzyl 3-(1,2-dihydroxyethyl)phenylcarbamate (8 g) was dissolved in dry DMF (50 mL) and cooled to 0° C. Imidazole (2.8 g) and TBSCl (5 g) were added and the mixture was stirred at room temperature for 24 hours. The reaction was quenched by addition of water (100 mL) and extracted with EtOAc (2×100 mL). The organic phase was separated, dried over Na2SO4 and concentrated to give a crude product which was purified by column chromatography to give the title compound (6 g, 60%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26]>O.O1CCCC1>[ClH:24].[CH3:30][CH:29]([CH3:31])[CH2:28][O:27][C:25]([NH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)=[O:26]
Reactant: CC(C)COC(=O)Cl
Reactant: N=C(Nc1cccc(N)c1)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COC(=O)Nc1cccc(NC(=N)N2CCCC2)c1
Temperature: 0 °C

Procedure:
A solution of the product of Example 1, step (b), 1.38 g, 0.0050 moles, was dissolved in 20 ml of water. The solution was gradually treated with sodium carbonate, 0.84 g, 0.0100 moles, and cooled to 0° C. A solution of 0.71 ml of isobutyl chloroformate in 10 ml of tetrahydrofuran was added. After 16 hours the mixture was diluted with water to 100 ml and washed with 20 ml of chloroform. This solution was then made basic with 50% aqueous sodium hydroxide and extracted with 20 ml chloroform (twice). The chloroform layer was dried over potassium carbonate, filtered and the solvent was driven off by vacuum evaporation. The remaining oil was dissolved in 20 ml of isopropanol and 1 ml of concentrated aqueous hydrochloric acid was added. The solution was then made up to 250 ml with ether. Crystals developed and were washed with 10 ml of ether (twice) and dried in a vacuum oven overnight to yield N-(3-(((2-methylpropyloxy)carbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide monohydrochloride. Yield: 1.1 g, m.p. 233°-235 ° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[C:13]([C:16]1[S:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].O>CN(C=O)C>[CH2:9]([O:8][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([C:19]2[S:20][C:16]([C:13](=[O:15])[CH3:14])=[CH:17][CH:18]=2)[CH:7]=1)[CH3:10]
Reactant: CCOc1cc(Cl)nc(SC)n1
Reactant: CC(=O)c1ccc(B(O)O)s1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2ccc(C(C)=O)s2)nc(SC)n1
Temperature: 80 °C
Yield: 27.9 %

Procedure:
The crude product of Preparation 27, 4-chloro-6-ethoxy-2-methylsulfanylpyrimidine, (525 mg, 2.56 mmol) was dissolved in DMF (4 mL). To this solution was added 5-acetyl-2-thiopheneboronic acid (523 mg, 3.08 mmol), PdCl2dppf (209 mg, 0.26 mmol), potassim carbonate (1.06 g, 7.69 mmol) and water (0.4 mL). The reaction mixture was heated at 80° C. under nitrogen atmosphere for overnight. The reaction mixture was cooled and poured into 30 mL of water and was then extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo. The resulting crude product was purified by flash silica column chromatography (20% ethyl acetate in hexane) to give product 1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone (210 mg, 28% yield over two steps). 1H-NMR (CDCl3): δ 7.67 (m, 2 H), 6.68 (s, 1 H), 4.46 (q, J=7.1 Hz, 2 H), 2.60 (s, 3 H), 2.59 (s, 3 H), 1.40 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [CH:1]([SiH:4]([CH:11]([CH3:13])[CH3:12])[C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O>ClC(Cl)C>[CH:11]([Si:4]([Br:14])([CH:1]([CH3:3])[CH3:2])[C:5]#[C:6][Si:7]([CH3:9])([CH3:8])[CH3:10])([CH3:13])[CH3:12]
Reactant: CC(C)[SiH](C#C[Si](C)(C)C)C(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(Cl)Cl
Product: CC(C)[Si](Br)(C#C[Si](C)(C)C)C(C)C
Yield: 87.9 %

Procedure:
Diisopropyl(trimethylsilylethynyl)silane (6.9 g, 33 mmol) was dissolved in dichloroethane (20 mL) in a round-bottom flask equipped with a stir bar and placed in an ice bath. N-Bromosuccinimide (36 mmol, 6.5 g) was added scoopwise over 30 minutes, and stirring was continued for 15 more minutes or until the solution began to turn bright orange. Solvent was removed using rotary evaporation, pentane was added to the resulting solid, and the remaining solid succinimide residues were removed by filtration. The pentane solution was again evaporated, the process repeated, and the pentane was removed to yield 8.6 g (29 mmol, 89%) of a product as a pale brown oil.
Reaction SMILES: ClC1C(Cl)=CC(NC2C3C(=CC(OCCOCC[O:29][S:30]([CH3:33])(=O)=[O:31])=C([N+]([O-])=O)C=3)N=CN=2)=C(F)C=1.[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][C:39]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][C:50]([O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][OH:69])=[C:51]([N+:54]([O-:56])=[O:55])[CH:52]=3)[N:47]=[CH:46][N:45]=2)=[C:38]([F:70])[CH:37]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][C:39]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][C:50]([O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][S:30]([CH3:33])(=[O:31])=[O:29])=[C:51]([N+:54]([O-:56])=[O:55])[CH:52]=3)[N:47]=[CH:46][N:45]=2)=[C:38]([F:70])[CH:37]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCO
Reactant: CS(=O)(=O)OCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCOCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]

Procedure:
Compound 32b was prepared as described hereinabove for Compound 32a, using Compound 29b (0.023 gram, 0.043 mmol), methanesulfonyl chloride (0.014 gram, 0.12 mmol) and triethylamine (0.021 gram, 0.021 mmol) in dichloromethane (2.3 ml), yielding 0.015 gram of the product (55% yield).
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.[CH2:10](N(CC)CC)C.IC>C(#N)C>[O:6]=[C:4]1[CH:1]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][O:5]1
Reactant: CCN(CC)CC
Reactant: O=C(O)C1(C(=O)O)CC1
Solvent: CC#N
Solvent: CI
Product: COC(=O)C1CCOC1=O
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Cyclopropane-1,1-dicarboxylic acid (10 g) in acetonitrile(200 ml) was treated with triethylamine (43 ml) and iodomethane (19 ml) at room temperature. The solution was stirred for 2 h then heated at 75° C. for 16 h. The solvent was removed under reduced pressure, the residue dissolved in water, extracted with ethyl acetate, dried(MgSO4) and evaporated to a brown oil (6.70 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH3:20])=[C:14]2[CH3:21])[CH3:5])[CH:2]=[CH2:3].F[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[C:15]([CH3:20])=[C:14]2[CH3:21])[CH3:5])[CH:2]=[CH2:3]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: C=CCN(C)CCCCOc1ccc2[nH]c(C)c(C)c2c1
Product: C=CCN(C)CCCCOc1ccc2c(c1)c(C)c(C)n2-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 9.1, Allyl-[4-(2,3-dimethyl-1H-indol-5-yloxy)-butyl]-methyl-amine and 1-Fluoro-4-trifluoromethyl-benzene were converted to yield Allyl-{4-[2,3-dimethyl -1-(4-trifluoromethyl-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine as yellow oil, MS: 431 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[N+:22]([C:25]1[CH:26]=[C:27](/[C:31](/[CH3:35])=[CH:32]/[CH2:33]O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]>C(#N)C>[Br:20][CH2:33]/[CH:32]=[C:31](/[C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=1)\[CH3:35]
Reactant: C/C(=C\CO)c1cccc([N+](=O)[O-])c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C/C(=C\CBr)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of triphenylphosphine (5.15 g, 19.7 mmol) in acetonitrile (140 ml) was added dropwise over 5 minutes a solution of bromine (3.15 g, 19.7 mmol) in acetonitrile (5 ml) at a rate such that the temperature did not exceed −10° C. The mixture was allowed to warm to room temperature, then to this was added a solution of (E)-3-(3-nitrophenyl)-2-buten-1-ol (Preparation 2, 4 g, 20.7 mmol) in acetonitrile (5 ml). The mixture was warmed gently to 65° C. for 1 h, cooled to room temperature and then poured onto diethyl ether (50 ml). The mixture was concentrated in vacuo, then diethyl ether (200 ml) was added. The mixture was filtered, concentrated again in vacuo and the residue purified by silica column (300 g) chromatography, eluting with 3:1 hexane/dichloromethane then 1:1 hexane/dichloromethane. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (4 g, 75%).
Reaction SMILES: C(N=S(C1C=CC(CN[C:13]([C:15]2[C:20](=[O:21])[C:19]([Br:22])=[C:18]([CH3:23])[N:17]([C:24]3[N:25]([CH3:29])[N:26]=[CH:27][CH:28]=3)[CH:16]=2)=[O:14])=CC=1)(C)=O)#N.C(N=S(C1C=CC(CN[C:44](C2C(=O)C=C(C)N(C3N(C)N=CC=3)C=2)=[O:45])=CC=1)(C)=O)#N.BrBr>>[CH3:44][O:45][C:13]([C:15]1[C:20](=[O:21])[C:19]([Br:22])=[C:18]([CH3:23])[N:17]([C:24]2[N:25]([CH3:29])[N:26]=[CH:27][CH:28]=2)[CH:16]=1)=[O:14]
Reactant: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=NC#N)cc2)cn1-c1ccnn1C
Reactant: Cc1cc(=O)c(C(=O)NCc2ccc(S(C)(=O)=NC#N)cc2)cn1-c1ccnn1C
Agent: BrBr
Product: COC(=O)c1cn(-c2ccnn2C)c(C)c(Br)c1=O

Procedure:
The title compound is prepared as described for preparation 4c, substituting preparation 4b with preparation 8.20a as starting material. ESI mass spectrum: [M+H]+=326 (bromine pattern); r.t. HPLC: 0.69 min (Z012_S04).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]#[CH:18].C(Cl)(Cl)Cl>CN(C)C=O>[C:1]([N:4]([C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[C:16]#[C:17][CH3:18])(=[O:3])[CH3:2]
Reactant: C#CCBr
Reactant: CC(=O)Nc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC#CN(C(C)=O)c1nc2ccccc2s1
Temperature: 50 °C
Yield: 62 %

Procedure:
2-Acetylaminobenzothiazole (e) (6.0 g) was dissolved in dimethylformamide (50 ml) and 50% sodium hydride (1.648 g) was added thereto in small portions with stirring under ice-cooling. The mixture was heated at 50° C. for 1 hour, then cooled to room temperature and 2-propynyl bromide (3.0 ml) was added thereto. The mixture was heated at 60° C. for 4 hours and evaporated to remove the solvent. After addition of water, the residue was extracted with benzene. The extract was washed with water, and evaporated to remove the solvent. The residue was applied to column chromatography on silica gel (120 g) to give 2-(N-acetyl-N-propynylamino)benzothiazole (f) (4.43 g, yield 62%) from chloroform eluate:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.ClC1C=C(C[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:18])C=CN=1>>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)c1)c1ccc(F)cc1
Reactant: Cc1ccnc(Br)c1
Product: O=C(Cc1ccnc(Br)c1)c1ccc(F)cc1

Procedure:
21c was prepared from 2-bromo-4-methylpyridine (9.6 g; 56 mmol) using the method described in the synthesis of 21a.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Li])(C)(C)C.C[O:21][B:22](OC)[O:23]C.Cl>C1COCC1>[C:4]([O:3][C:1]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[B:22]([OH:23])[OH:21])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Temperature: -20 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a cooled (-78° C.) solution of N-BOC aniline (5 g1 25.87 mmol) in THF (111.1 mL) was added tert-butyl lithium (38.9 mL, 66.7 mmol) and the mixture was stirred under an argon atmosphere for E5 min. It was then allowed to warm up to -20° C. and stirred at that temperature for 2 h. Trimethylborate was added (11.94 mL, 105.6 mmol) and the mixture was stirred until it warmed up to room temperature. Then, it was cooled to 0° C. and aqueous 10% HCl was added to pH=6.5. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried and concentrated to a crude product, which was washed with a mixture of EtOAc-hexane (5:95) to give the title compound as a yellow solid (53%).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:5]=[C:6]([OH:19])[C:7](=[CH:17][CH:18]=1)[CH:8]=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH3:2].[CH:22](=O)[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[OH:25]>C(O)C>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([OH:19])[C:7](=[CH:17][CH:18]=1)[CH:8]=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[CH:22][C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[OH:25])[CH3:21]
Reactant: O=Cc1ccccc1O
Reactant: CCN(CC)c1ccc(C=Nc2ccccc2N)c(O)c1
Solvent: CCO
Product: CCN(CC)c1ccc(C=Nc2ccccc2N=Cc2ccccc2O)c(O)c1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
To a yellowish brown suspension of 0.3 g (1.06 mmol) N-Mono[4-(diethylamino)-salicylidene]-1,2-phenylenediamine from example 30 in 2 ml ethanol are added dropwise at 60° C. 129 mg (112 μl, 1.06 mmol) salicylaldehyde. The reaction slolution is stirred for 5 hours at 75° C. and after cooling to room temperature concentrated to dryness. The crude product is resolved by column chromatography (n-hexane/ethyl acetate 65:35). Yield: 139 mg (34%), colourless oil.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([F:4])[F:3].C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][C:2]([S:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:15][C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1)([F:4])[F:3]
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(SC(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A mixture of 5.42 g (26.3 mmol) 4-trifluoromethylsulfanyl-benzaldehyde, 3.12 g (30.0 mmol) malonic acid, 0.26 g (3.0 mmol) piperidine and 12.0 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (5 h). The reaction mixture was poured into a solution of 50 ml ice water and 15 ml 6N HCl. The precipitate was isolated, washed with water, then with n-heptane and dried at 50° C. Yield: 5.9 g (85%) 3-(4-Trifluoromethylsulfanyl-phenyl)-acrylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-])=O.C(O)C.O.O.[Sn](Cl)Cl>C(=O)(O)[O-].[Na+]>[CH2:11]1[C:12]2[NH:13][C:14]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=3)[C:7]=2[CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2[nH]c3c(c2c1)CCCC3
Temperature: 70 °C
Yield: 95.3 %

Procedure:
6-Nitro-2,3,4,9-tetrahydro-1H-carbazole (0.100 g, 0.462 mmol) was dissolved in a 40 mL scintillation vial containing a magnetic stir bar and 2 mL of ethanol. Tin (II) chloride dihydrate (1.04 g, 4.62 mmol) was added to the reaction mixture and the resulting suspension was heated at 70° C. for 16 h. The crude reaction mixture was then diluted with 15 mL of a saturated aqueous solution of sodium bicarbonate and extracted three times with an equivalent volume of ethyl acetate. The ethyl acetate extracts were combined, dried over sodium sulfate, and evaporated to dryness to yield 2,3,4,9-tetrahydro-1H-carbazol-6-amine (82 mg, 95%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:20](O)=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.ClC(OCC)=O.[CH2:36]([NH:38][CH:39]([CH3:41])[CH3:40])[CH3:37]>O1CCCC1>[CH2:36]([N:38]([CH:39]([CH3:41])[CH3:40])[C:20]([C:12]1[N:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:19]2[C:14]([CH:13]=1)=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:21])[CH3:37]
Reactant: COc1ccc(-n2c(C(=O)O)cc3ccccc32)cc1OC
Reactant: CCNC(C)C
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(C(=O)c1cc2ccccc2n1-c1ccc(OC)c(OC)c1)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(3,4-Dimethoxyphenyl)indole-2-carboxylic acid (2.0 g, 6.8 mmol) was stirred in tetrahydrofuran (10 ml). Triethylamine (1 ml, 7.5 mmol) was added and the mixture was cooled to 0° C. Ethyl chloroformate (0.7 ml, 7 mmol) was added dropwise, followed by stirring for 30 minutes. N-ethyl isopropylamine (0.6 g, 7 mmol) in tetrahydrofuran was added, followed by stirring for 30 minutes and refluxing for 6 hours. The tetrahydrofuran was evaporated in vacuo, and the residue was dissolved in toluene. The toluene solution was washed with water, dried, evaporated in vacuo, applied onto a flash chromatography column (silica gel, 30 g) and eluted with toluene/acetone (9.5:0.5). The desired fractions were concentrated and the residue triturated with diisopropyl ether to give 1-(3,4-dimethoxyphenyl)indole-2-carboxylic acid N-ethyl isopropyl amide as white crystals which were then filtered and dried. Yield: 50 mg (2% of theoretical). Rf : 0.53 (toluene/acetone 7:3). The H-NMR spectra was consistent with the assigned structure.