Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[CH:9])[CH3:5])[CH3:2].C([Li])CCC.[CH3:15][S:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:21]([C:20]1[CH:23]=[CH:24][C:17]([S:16][CH3:15])=[CH:18][CH:19]=1)[OH:22])[CH3:5])[CH3:2]
Reactant: CSc1ccc(C=O)cc1
Reactant: C#CCOC(C)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(C)OCC#CC(O)c1ccc(SC)cc1
Reaction time: 0.5 h

Procedure:
A solution of 8 g (62.4 mmol) of 1-(1-ethoxyethoxy)-2-propyne in 135 ml of tetrahydrofuran was treated at -78° under argon with 39 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -40° for 30 minutes and then a solution of 8.11 ml (62.4 mmol) of 4-(methylthio)benzaldehyde in 53 ml of tetrahydrofuran was added within 10 minutes. The reaction mixture was warmed to 0°, stirred at 0° for a further 1 hour and then treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 600 g of silica gel (elution agent ether/hexane 1:1). There was obtained 4-(1-ethoxyethoxy)-1- [4-(methylthio)phenyl]-2 -butyn-1 ol as an oil.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9]([CH2:12][C:13](=[NH:17])OCC)[C:8]=2[CH:18]=1.[CH2:19](N)[CH2:20][NH2:21].Cl>C(O)C>[ClH:1].[NH:21]1[CH2:20][CH2:19][N:17]=[C:13]1[CH2:12][C:9]1[C:8]2[CH:18]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=2[O:11][N:10]=1
Reactant: NCCN
Reactant: CCOC(=N)Cc1noc2ccc(OC)cc12
Agent: Cl
Solvent: CCO
Product: COc1ccc2onc(CC3=NCCN3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 120.4 %

Procedure:
In ethanol (20 ml) was dissolved ethyl 5-methoxy-1,2-benzisoxazole-3-acetimidate hydrochloride (2.1 g) and thereto was added ethylenediamine (0.59 g) at room temperature. The mixture was stirred at room temperature for 3 hours and then kept in refrigerator overnight. To the mixture was added ethanol (10 ml) containing 20 % hydrochloric acid, and the precipitated crystallines were separated by filtration, washed with ether, dried and recrystallized from ethanol to give the desired compound (2.5 g). m.p. 240° to 252°C (decomp).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9](Cl)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.[O-:17][C:18]#[N:19].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([N:19]=[C:18]=[O:17])[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NC(Cl)C(Cl)(Cl)Cl)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)NC(N=C=O)C(Cl)(Cl)Cl)cc1
Reaction time: 12 h
Yield: 60.7 %

Procedure:
A stirred solution of Example 37D (1.00 g, 3.32.00 mmol) in acetone (20 mL) at ambient temperature was treated with potassium cyanate (1.60 g, 16.0 mmol). The reaction mixture was stirred for 12 hours, concentrated, and the crude residue was purified by flash chromatography (elution with 50% ethyl acetate/hexanes) to provide 620 mg of the desired product as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:10](=[N:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(N=Cc2ccccc2)cc1Cl

Procedure:
Equimolar amounts of 3,4-dichloroaniline and benzaldehyde are stirred together at room temperature to give a nearly quantitative yield of N-benzylidene-3,4-dichloroaniline that melts at 62°-5° C. upon recrystallization from ethanol.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:32])[CH2:9][N:10]2[C:15]3=[N:16][C:17]([N:21]4[CH2:26][C@@H:25]5[CH2:27][C@H:22]4[CH2:23][O:24]5)=[CH:18][C:19](=[O:20])[N:14]3[CH2:13][CH2:12][C@H:11]2[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1.[CH2:33]([CH2:35][NH2:36])[OH:34]>C(O)C>[OH:34][CH2:33][CH2:35][NH:36][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:32])[CH2:9][N:10]2[C:15]3=[N:16][C:17]([N:21]4[CH2:26][C@@H:25]5[CH2:27][C@H:22]4[CH2:23][O:24]5)=[CH:18][C:19](=[O:20])[N:14]3[CH2:13][CH2:12][C@H:11]2[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1
Reactant: O=C(CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccc(Cl)nc1
Reactant: NCCO
Solvent: CCO
Product: O=C(CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccc(NCCO)nc1
Temperature: 130 °C
Yield: 49.1 %

Procedure:
A mixture of 0.50 mL of ethanol, 33 mg (0.070 mmol) of (8S)-9-[2-(6-chloropyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 21.41 μl (0.352 mmol) of ethanolamine is heated in a Biotage microwave reactor at 130° C. for 30 minutes. The reaction mixture is evaporated to dryness and the residue is then taken up in 10 mL of water. The precipitate is filtered off and then dried under vacuum. 17 mg of (8S)-9-{2-[6-(2-hydroxyethylamino)pyrid-3-yl]-2-oxoethyl}-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:6]=CC=1)#N.[C:18]([OH:21])(=[O:20])[CH3:19].Cl>>[C:18]([C:19]1[CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=[CH:3][CH:1]=1)([OH:21])=[O:20]
Reactant: N#Cc1cccc(-c2ccnc3ccnn23)c1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)c1cccc(-c2ccnc3ccnn23)c1

Procedure:
A sample of 7-(m-cyanophenyl)pyrazolo[1,5-a]pyrimidine is heated with acetic acid-hydrochloric acid to give 7-(m-carboxyphenyl)pyrazolo[1,5-a]pyrimidine. The preceding compound is heated with sulfur tetrafluoride for 20 hours at 150° C. to give the product of the example, m.p. 104°-106° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH3:28]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:28][CH2:27][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Reactant: CC(I)C1CCCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(CCC4CCCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 35 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and (1-iodoethyl)cyclohexane.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N:15][O:16][CH2:17][CH2:18][OH:19])[CH3:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N:15][O:16][CH2:17][CH2:18][O:19][C:21]3[CH:53]=[CH:52][C:24]([CH2:25][CH:26]4[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=5)[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]4=[O:51])=[CH:23][CH:22]=3)[CH3:14])=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(-c2ccccc2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccccc2)nc1
Yield: 86 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 384 mg of 2-[1-(2-phenyl-5-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 17), 537 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 393 mg of triphenylphosphine and 261 mg of diethyl azodicarboxylate, 698 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:19]=[CH:20][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[N:22][CH:23]=1>>[CH3:39][C:33]1[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=1[N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:21]2[CH:20]=[CH:19][C:18]([N:11]3[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]3(=[O:15])=[O:16])=[CH:23][N:22]=2)=[O:25])[CH2:31][CH2:30]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 41.8 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (439 mg) described in Preparation Example 1 and (5-bromopyridin-2-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (680 mg) described in Preparation Example 137 and by the reaction and treatment in the same manner as in Example 32, the title compound (338 mg) was obtained.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[C:18]([CH:19]=[O:20])=[CH:17][NH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:13][C:14]1[C:18]([CH:19]=[O:20])=[CH:17][N:16]([C:2]2[C:7]([CH:8]3[CH2:12][CH2:11][CH2:10][O:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)[N:15]=1
Reactant: Fc1ncccc1C1CCCO1
Reactant: Cc1n[nH]cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ncccc2C2CCCO2)cc1C=O
Temperature: 110 °C
Reaction time: 18 h
Yield: 60.9 %

Procedure:
To a screw-cap test tube containing 2-fluoro-3-(tetrahydrofuran-2-yl)pyridine (148 mg, 0.88 mmol) in dimethylformamide (2.2 mL) are added 3-methyl-1H-pyrazole-4-carbaldehyde (81 mg, 0.74 mmol) and potassium carbonate (152 mg, 1.1 mmol). The reaction tube is quickly sealed (caution: build-up of pressure possible; use a safety shield) and stirred in a preheated oil bath at 110° C. for 18 h with the aid of a magnetic stirrer. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is separated, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The resulting residue is purified by silica gel using normal phase Isco chromatography eluting with hexane: acetone (gradient from 5 to 20% in acetone) to give 116 mg of the title compound. MS (m/z): 258 (M+1).
Reaction SMILES: C([O:3][C:4](=[CH:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:5]([F:8])([F:7])[F:6])C.S(=O)(=O)(O)O>CCOCC.O>[C:13]1(=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][C:4]([C:5]([F:7])([F:6])[F:8])=[O:3])[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]12
Reactant: CCOC(=CCCN1C(=O)c2ccccc2C1=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCC(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 20 mmole of N-(3-bromopropyl)phthalimide and 22 mmole of triphenylphosphine in 50 ml of benzene is heated at reflux temperature for 2 days. The solid which separates on cooling is filtered, washed with benzene and dried under reduced pressure to give 3-phthalimidopropyl triphenylphosphonium bromide. To a solution of 100 ml of dry liquid ammonia is added finely divided sodium (0.46 g or 2 × 10-2M) and a catalytic amount of ferric nitrate. When the blue sodium solution turns gray 10 g or 2 × 10-2M of finely powdered 3-phthalimidopropyltriphenylphosphonium bromide is added. After stirring for 15 minutes the ammonia is evaporated under a stream of nitrogen. To the residue is added 100 ml of anhydrous benzene and the solution is boiled for about 10 minutes under nitrogen. The solid residue is filtered pff and to the filtrate, containing salt free 3-phthalimidopropylidene triphenylphosphorane is added 6.6 g of 5 × 10-2M of ethyl trifluoroacetate. The reaction mixture is heated at reflux temperature under nitrogen for 12 hours. Concentration of the solvent leaves a residue which is distilled under high vacuum to afford 2-ethoxy-1,1,1-trifluoro-5-phthalimidopent-2ene. A solution of 3 g of 2-ethoxy-1,1,1-trifluoro-5-phthalimidopent- 2-ene in 50 ml of ether is treated with a solution of 1 M of sulfuric acid in 50 ml of water. The reaction mixture is stirred for one half hour at 25° C. The ether phase is separated, washed with brine, and dried over magnesium sulfate and concenrated to give trifluoromethyl 3-phthalimidopropyl ketone.
Reaction SMILES: [C:1]12[C:18](=[O:19])[O:17][C:15](=O)[C:13]3=[C:14]1[C:5](=[CH:6][C:7]1[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:4]=[CH:3][CH:2]=2.[CH2:20]([CH2:22][NH2:23])[OH:21]>C1(C)C=CC=CC=1>[OH:21][CH2:20][CH2:22][N:23]1[C:18](=[O:19])[C:1]2[CH:2]=[CH:3][CH:4]=[C:5]3[C:14]=2[C:13](=[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=[CH:6]3)[C:15]1=[O:17]
Reactant: NCCO
Reactant: O=C1OC(=O)c2c3ccccc3cc3cccc1c23
Solvent: Cc1ccccc1
Product: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCO
Temperature: 25 °C
Yield: 85.8 %

Procedure:
A mixture of 1.51 g (6 mmol) of anthracene-1,9-dicarboxylic acid anhydride and 0.4 g (6.5 mmol) of ethanolamine in 50 ml of toluene is refluxed for 5 hours and then cooled to room temperature. The solid is filtered, dried and crystallized from toluene to give 1.5 g (85%) of 2-(2-hydroxyethyl)-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione. M.p. 211° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[Br:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1>>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][CH:2]([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][CH:22]=1
Reactant: Brc1ccc(Br)cc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Product: Cc1c(C)c(N2CCN(c3ccc(Br)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 55.4 %

Procedure:
By using 1-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (2.60 g, 10.0 mmol) synthesized in Reference example 56 and 1,4-dibromobenzene (7.08 g, 30 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 2.3 g (yield 55%). Melting point was 202 to 204° C. (hexane-ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:25](=[O:32])[C:26]5[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Agent: Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cccnc4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-nicotinamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (200 mg, 0.64 mmol) and nicotinoyl chloride hydrochloride (282 mg, 1.93 mmol). The title compound was obtained as pink powder (94 mg, 35%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]=[C:20]([C:22]([OH:24])=O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Cl.[OH:26][C:27]1[C:36]([N:37]([CH3:39])[CH3:38])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[C:1]([NH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]=[C:20]([C:22]([N:31]3[CH2:30][CH2:29][C:28]4[C:33](=[CH:34][CH:35]=[C:36]([N:37]([CH3:39])[CH3:38])[C:27]=4[OH:26])[CH2:32]3)=[O:24])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: CC(=O)NCc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: CC(=O)NCc1ccc(-c2nc(C(=O)N3CCc4c(ccc(N(C)C)c4O)C3)c3ccccc3n2)cc1
Yield: 5 %

Procedure:
Reaction of 2-(4-(acetamidomethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 68 (5% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.91 (s, 3H), 2.56 and 2.60 (2s, 6H), 2.63 and 2.90 (2t, 2H), 3.48 and 4.04 (2t, 2H), 4.34-4.37 (m, 2H), 4.39 and 4.92 (2s, 2H), 6.31-7.02 (m, 2H), 7.41-7.47 (m, 2H), 7.66-7.78 (m, 1H), 7.88-7.98 (m, 1H), 8.02-8.17 (m, 2H), 8.43-8.51 (m, 3H); MS (ESI) m/z 496 ([M+H]+).
Reaction SMILES: C([O:3][C:4](=[S:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])C.O.[OH-].[K+].Cl>C1COCC1>[CH2:11]([CH:5]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:4]([OH:3])=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=S)C(Cc1ccccc1)CC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CC(Cc1ccccc1)C(O)=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 g of 2-benzyl-3-tert.-butylthio-propionic acid ethyl ester is dissolved in 5 ml of THF, and 3.2 ml of water and 0.9 ml of 2N potassium hydroxide solution are added thereto. The mixture is stirred overnight at room temperature, neutralised with 0.9 ml of 2N hydrochloric acid and concentrated by evaporation. The residue is purified by flash chromatography on 30 g of silica gel 60 (eluant H). Yellow oil, 1H-NMR (DMSO-d6): 1.23 ppm (s, 9H); 2.55-2.9 (m, 5H); 7.15-7.3 (m, 5H); 12.4 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=4)[CH:16]=3)[S:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=4)[CH:16]=3)[S:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)nc2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cn1
Temperature: 35 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of ethyl 4-[[4-(6-methylpyridin-3-yl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 233, 70.0 mg, 0.159 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was stirred overnight at 35° C. Upon cooling to room temperature, the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from acetone to give 60.0 mg (92%) of the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.36 (1H, d, J=2.1 Hz), 7.91 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.56 (1H, dd, J=2.1 8.0 Hz), 7.45 (2H, m), 7.31 (1H, d, J=8.0 Hz), 7.06 (1H, s), 6.06 (1H, s), 2.51 (3H, s), 1.44 (6H, s).
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([NH:12][C:13]4[S:21][C:16]5[CH2:17][O:18][CH2:19][CH2:20][C:15]=5[C:14]=4[C:22](O)=[O:23])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.[F:25][C:26]([F:31])([F:30])[CH2:27][CH2:28][NH2:29]>>[CH2:7]1[CH:8]2[C:4]3([C:10]([NH:12][C:13]4[S:21][C:16]5[CH2:17][O:18][CH2:19][CH2:20][C:15]=5[C:14]=4[C:22]([NH:29][CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])=[O:23])=[O:11])[CH2:3][CH:2]([CH2:9][CH:6]1[CH2:5]3)[CH2:1]2
Reactant: O=C(O)c1c(NC(=O)C23CC4CC(CC2C4)C3)sc2c1CCOC2
Reactant: NCCC(F)(F)F
Product: O=C(NCCC(F)(F)F)c1c(NC(=O)C23CC4CC(CC2C4)C3)sc2c1CCOC2

Procedure:
The title compound was prepared from 2-[(hexahydro-2,5-methano-pentalene-3a-carbonyl)-amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid. (Example 10A) and 3,3,3-trifluoropropylamine according to the procedure described for Example 166C. 1H NMR (DMSO-d6, 300 MHz) δ 1.62-1.67 (m, 4H), 1.76-1.88 (m, 4H), 1.98-2.02 (m, 2H), 2.33 (br s, 2H), 2.51-2.63 (m, 3H), 2.81 (t, J=5.3 Hz, 2H), 3.52 (q, J=6.8 Hz, 2H), 3.85 (t, J=5.4 Hz, 2H), 4.65 (br s, 2H), 7.50 (t, J=5.6 Hz, 1H), 11.83 (br s, 1H). MS (ESI+) m/z 443.1 (M+H)+. Anal. calcd. for C21H25F3N2O3S: C, 57.00; H, 5.69; N, 6.33. Found: C, 57.24; H, 5.56; N, 6.27.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]1>>[CH3:13][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]3)=[CH:3][CH:4]=2)=[N:12][N:11]=1
Reactant: Cc1nnc(-c2ccc(Br)cc2)o1
Reactant: OC1CCCNC1
Product: Cc1nnc(-c2ccc(N3CCCC(O)C3)cc2)o1
Yield: 36.9 %

Procedure:
1-(4-(5-Methyl-1,3,4-oxadiazol-2-yl)phenyl)piperidin-3-ol (120 mg, 0.463 mmol, 37% yield) was synthesized as described in General Procedure B using 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole (300 mg, 1.255 mmol) and piperidin-3-ol (254 mg, 2.51 mmol). Anal. Calcd. for C14H17N3O2 m/z 259.3, found: 260.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+]([O-])=O)=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.O=P(Cl)(Cl)[Cl:15]>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Solvent: ClCCl
Product: Cc1cc(Cl)c(Br)c[n+]1[O-]
Yield: 79.5 %

Procedure:
To a solution of 5-bromo-2-methyl-4-nitropyridine N-oxide (558 mg, 2.41 mmol) in DCM (3 mL) at 0° C. was added dropwise a solution of POCl3 (1.3 mL, 7.22 mmol) in DCM (3.2 mL). After 12 h at 25° C. the solution was added to ice, adjusted to pH ˜8 and extracted several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 1.5% MeOH in DCM) yielding the title compound (426 mg, 80%) as a white solid: LCMS (ES) m/z=224 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18](O)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:21])[C:18]([NH:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)=[O:19])[CH2:15][CH2:16]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)Nc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
To a stirred solution of 2-(4-(2-tert-butylphenyl)piperazin-1-yl)-2-oxo-acetic acid (0.086 g, 0.30 mmol) in methylene chloride (4.0 mL) was added EDCI (0.75 g, 0.39 mmol) and HOBt (0.053 g, 0.39 mmol) at room temperature. After 30 min 2-aminopyridine (0.031 g, 0.33 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After this time, the reaction mixture was concentrated under reduced pressure and the residue purified by flash column chromatography (silica gel, 80:20 heptane/ethyl acetate) to provided 2-(4-(2-tert-butylphenyl)piperazin-1-yl)-2-oxo-N-(pyridin-2-yl)acetamide (0.043 g, 39%) as a white solid, mp 168-172° C.