Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].Cl>CN(C)C(=O)C>[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:29][CH:30]=1)(=[O:24])=[O:23]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Cc1ccccc1S(=O)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a stirred, cooled (-15° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methyl propanoic acid (1.42 g, 9.0 mmol) in N,N-dimethylacetamide (13 mL) was rapidly added thionyl chloride (1.13 g, 9.5 mmol) and the mixture (a precipitate formed after a few minutes) stirred at -20° C. to -10° C. for 1 hour. 4-(2-Methylphenylsulfonyl)benzenamine (1.48 g, 6.0 mmol) was then added in one portion, washed in with 2 mL of N,N-dimethylacetamide and the mixture allowed to stir at room temperature overnight. The solution was poured into water, the cloudy solution decanted from the resulting gum and filtered through a thin pad of Celite. The Celite pad was washed with methylene chloride and the solution added to a solution of the gum in methylene chloride. The combined methylene chloride solution was dried (MgSO4), filtered and the solvent removed in vacuo. The resulting gum was dissolved in a few mL of methanol and added dropwise to 100 mL of rapidly stirred 3N HCl . The aqueous phase was decanted from the gum, the gum dissolved in methylene chloride, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was dissolved in 125 mL of methylene chloride and heated on a steam bath as 100 mL of hexane was slowly added to replace the methylene chloride. When a volume of 125 mL was reached more hexane (ca. 50 mL) was added to the cloud point. After cooling overnight the resulting solid was filtered to yield impure product. This material was further stirred with 300 mL of 0.5N HCl for 45 min., the aqueous phase decanted off and the residual gum dissolved in methylene chloride, dried (MgSO4), filtered and the solvent removed in vacuo. The material was dissolved in 100 mL of methylene chloride, 50 mL of hexane added and the solution heated on a steam bath to a final volume of 100 mL. After cooling the resulting solid was filtered and dried at 100°-120° C./0.1 torr. for 2.5 hours to yield the title propanamide (1.78 g, 77%) as a light tan solid; mp 126°-128° C. 1H-NMR (300 MHz, d6 -DMSO): 1.58 (s, 3H, CH3), 2.39 (s, 3H, aryl CH3), 7.37-8.10 (m, 8H, aromatic), 7.6 (broad s, 1H, OH), 10.4 (broad s, 1H, NH). MS (CI, CH4): 388(M+1). Analysis for C17H16F3NO4S: Calculated: C, 52.71; H, 4.16; N, 3.62 Found: C, 52.64; H, 4.16; N, 3.59
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[NH:23][C:15]3=[N:16][CH:17]=[C:18]([N+:20]([O-])=O)[CH:19]=[C:14]3[CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Cl.O>C(O)C.[Fe]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[NH:23][C:15]3=[N:16][CH:17]=[C:18]([NH2:20])[CH:19]=[C:14]3[CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COCCOc1cccc(-c2cc3cc([N+](=O)[O-])cnc3[nH]2)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COCCOc1cccc(-c2cc3cc(N)cnc3[nH]2)c1
Temperature: 70 °C
Yield: 59.7 %

Procedure:
To a mixture of 2-[3-(2-methoxy-ethoxy)-phenyl]-5-nitro-1H-pyrrolo[2,3-b]pyridine (7.1 mmol, 2.2 g) and iron powder (6.7 g) in ethanol (50 mL) was added HCl (conc.) (0.7 mL) and water (5 mL). The mixture was heated at 70° C. for 3 hours then cooled and filtered through Celite®. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (30 mL), washed with saturated sodium bicarbonate (15 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, ethyl acetate) to afford 2-[3-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-5-ylamine (1.2 g, 60%).
Reaction SMILES: [C:1]([CH2:9][C:10]([O-:12])=O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:13][NH:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>O>[CH3:13][N:14]1[C:1]([C:2]2[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=2)=[CH:9][C:10](=[O:12])[N:15]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNNc1ccccc1
Reactant: O=C([O-])CC(=O)c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(-c2ccncc2)cc(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
thyl isonicotinoylacetate (3.01 g, 16 mmol) and 1-methyl-2-phenylhydrazine (2.03 g, 17 mmol) were suspended in water (50 ml) and glacial acetic acid (1.35 ml, 23 mmol) was added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (115 C) and stirred. After 4 hours, the reaction cooled to room temperature and extracted with EtOAc (2×100 ml; 50 ml), 10:1 DCM/MeOH (110 ml), and EtOAc again. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude material was purified on silica gel (DCM->20:1->10:1 DCM/MeOH->10:1->4:1 DCM/2 N ammonia in MeOH). Fractions with product collected, concentrated, and repurified on silica gel using DCM->20:1 DCM/MeOH->5:1 DCM/2 N ammonia in MeOH). The fractions with product were collected and concentrated to give 1-methyl-2-phenyl-5-(pyridin-4-yl)-1,2-dihydropyrazol-3-one (3.31 g, 70% purity, 9.2 mmol, 59%). MS (ESI pos. ion) m/z: 252 (MH+). Calc'd exact mass for C15H13N3O: 251.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH2:32]([S:34]([Cl:37])(=[O:36])=[O:35])[CH3:33]>>[ClH:37].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])=[C:3]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:24])=[O:25])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1ccc(N2CCCNCC2)cc1NS(=O)(=O)c1ccccc1
Product: Cl

Procedure:
N-{5-(1,4-diazepan-1-yl)-2-[(ethylsulfonyl)amino]phenyl}benzenesulfonamide hydrochloride was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide (0.085 g, 0.19 mmol) and ethanesulfonyl chloride (0.032 μL, 0.25 mmol) to give 29.1 mg of a light purple solid; Anal. (C24H27ClN4O3S×0.75H2O) C, H, N, S.; M+ 439.4 Calcd 439.14.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([CH3:19])[CH:21]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: Cc1cccc(C(=O)Cl)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(C)c3)CC2)ccc1Cl
Yield: 56 %

Procedure:
The title compound (22 mg, 56%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 3-methylbenzoyl chloride. MS:387.4 (MH+)
Reaction SMILES: [OH:1][C:2]1[CH:41]=[CH:40][C:5]2[CH:6]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH:19]=3)[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C[OH:43]>O>[OH:1][C:2]1[CH:41]=[CH:40][C:5]2[CH:6]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([CH2:30][CH2:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:35])([F:36])[F:37])=[O:43])[CH:19]=3)[C:7]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1cccc(OCCCCSCCCC(F)(F)C(F)(F)F)c1
Reactant: CO
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1cccc(OCCCCS(=O)CCCC(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[3-(4-(4,4,5,5,5-pentafluoropentylthio)butyloxy)phenyl]-2,3-dihydro-4H-benzopyran (72 mg, 0.12 mmol) was dissolved in methanol (5 ml) and water (1 ml), and NaIO4 (35 mg, 0.16 mmol) was added thereto. The reaction solution was stirred for 12 hours at room temperature and then extracted with ethyl acetate. The organic layer thus separated was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography (n-hexane:ethyl acetate=2:1) to obtain 66 mg (yield: 89%) of the title compound as a white foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=1.[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH2:27]>>[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH:27][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:13][N:12]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CSc1ncc(Cc2ccccn2)c(=O)[nH]1
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccccn2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone (4.7 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (3.4 g) was heated at 130°-135° for 7 hours. The cooled residue was triturated with hot water to give 2-[2-(5-methyl-4- imidazolylmethylthio)ethylamino]-5-(2-pyridylmethyl)-4-pyrimidone and this product was treated with dilute ethanolic HCl to give the title compound m.p. 207°-210° (aqueous ethanol)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:8]=[C:9]2[NH:17][CH:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]2[C:11](=[O:13])[CH:12]=1.[OH-].[Na+]>ClCCCl.O.C(OCC)(=O)C>[Cl:3][C:7]1[N:8]=[C:9]2[NH:17][CH:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]2[C:11](=[O:13])[CH:12]=1
Reactant: O=c1cc(O)nc2n1CCC(C(F)(F)F)N2
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: O=c1cc(Cl)nc2n1CCC(C(F)(F)F)N2
Temperature: 65 °C
Yield: 81.6 %

Procedure:
136 mL (1440 mmol) of phosphorus oxychloride are added, at room temperature and under an argon atmosphere, to a suspension of 68.10 g (290 mmol) of 2-hydroxy-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 950 mL of 1,2-dichloroethane. The mixture obtained is then heated at 65° C. for 3 hours. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 140 mL of cold water and 430 mL of ethyl acetate. 32% sodium hydroxide is added to the mixture obtained, to pH=5. The resulting organic phase is separated out and then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 60 g of 2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in the form of an orange solid, the characteristics of which are as follows:
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].CS([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=O)=O>>[CH:1]([S:4]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Product: CC(C)S(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Yield: 83 %

Procedure:
Isopropylsulfonyl chloride (70 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (80 mg, 0.203 mmol, 83% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.78 (s, 1H), 7.57 (s, 4H), 6.38 (d, J=7.5 Hz, 1H), 4.19 (d, J=Hz, 1H), 3.82 (d, J=Hz, 1H), 3.73 (m, 1H), 3.18 (t, J=12.4 Hz, 1H), 2.82 (m, 1H), 2.78 (t, J=Hz, 1H), 1.80 (t, J=9.6, 2H), 1.43 (m, 2H), 0.97 (s, 6H).
Reaction SMILES: O.[C:2]([OH:12])(=[O:11])[C:3]1[C:4](=[CH:6][C:7](=[CH:9][CH:10]=1)[OH:8])[OH:5].[Bi]=O.[Bi:15]>C(O)C>[C:2]([O-:12])(=[O:11])[C:3]1[C:4](=[CH:6][C:7](=[CH:9][CH:10]=1)[OH:8])[OH:5].[Bi+3:15].[C:2]([O-:12])(=[O:11])[C:3]1[C:4](=[CH:6][C:7](=[CH:9][CH:10]=1)[OH:8])[OH:5].[C:2]([O-:12])(=[O:11])[C:3]1[C:4](=[CH:6][C:7](=[CH:9][CH:10]=1)[OH:8])[OH:5]
Reactant: [Bi]
Reactant: O=C(O)c1ccc(O)cc1O
Agent: O=[Bi]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1ccc(O)cc1O
Product: [Bi+3]
Temperature: 50 °C

Procedure:
A hydroalcoholic mixture consisting of 600 ml of distilled water and 600 ml of ethanol is made up in the same reactor as in Example 1 and then 46.24 g of β-resorcylic acid, that is 0.3 moles are introduced into it. The mixture is heated to 50° C. with stirring. The acid dissolves completely. 69.9 g of bismuth oxide, that is 0.3 gram-atoms of bismuth, are then introduced, as according to Example 1. The suspension is heated to 80° C. and kept stirred at this temperature for approximately 5 hours, after which the suspension is treated as according to Example 1: filtration followed by vacuum-drying.
Reaction SMILES: C(C1C=CC([C:9]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[O:12][C:11]([CH3:22])([CH3:21])[CH:10]=2)=C(OC)C=1)#N.CC1(C)CC(C2C=CC=CN=2)C2C=C(C(O)=O)C=CC=2[O:27]1.C[C:47](C)([O:50][C:51]1[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[CH:53][CH:52]=1)C#C>C(NCC)C.[Pd](Cl)Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][C:11]([CH3:21])([CH3:22])[C:10]#[C:9][O:27][C:52]2[CH:53]=[C:54]([CH:57]=[CH:58][C:51]=2[O:50][CH3:47])[C:55]#[N:56])=[CH:18][CH:17]=1)#[N:20]
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Reactant: COc1cc(C#N)ccc1C1=CC(C)(C)Oc2ccc(C#N)cc21
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(=O)O)ccc2O1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COc1ccc(C#N)cc1OC#CC(C)(C)Oc1ccc(C#N)cc1
Reaction time: 48 h

Procedure:
The 4-(4-cyano-2-methoxyphenyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile used as the starting material was prepared as follows: (A) 5.18 g of 3-iodo-4-methoxybenzonitrile were added at room temperature to a solution of 18 mg of palladium(II) chloride, 52 mg of triphenylphosphine and 38 mg of copper(I) iodide in 100 ml of diethylamine. 3.7 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile were added and the mixture was stirred under a nitrogen atmosphere for 2 days. The mixture was evaporated and the residue was dissolved in ethyl acetate and water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) for the elution to give 4.8 g of 3-[3-(4-cyanophenoxy)-3-methyl-1-butyn-1-yloxy]-4-methoxybenzonitrile as a solid which was used without further purification. (B) 4.8 g of 3-[3-(4-cyanophenoxy)-3-methyl-1-butyn-1-yloxy]-4-methoxybenzonitrile was heated at reflux for 2.5 hours in 50 ml of 1,2-dichlorobenzene and then allowed to cool to room temperature. The mixture was evaporated and the residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) for the elution. The product was recrystallized from isopropanol to give 3.8 g of 4-(4-cyano-2-methoxyphenyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile of melting point 137°-139° C.
Reaction SMILES: C(N1CCNC1=NC#N)C1C=CC=CC=1.[CH2:16]([N:23]1[CH2:27][CH2:26][NH:25][S:24]1(=[O:29])=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:30]([NH:37][C:38]([C:40]1[S:44][C:43](Br)=[N:42][C:41]=1[CH3:46])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([NH:37][C:38]([C:40]1[S:44][C:43]([N:25]2[CH2:26][CH2:27][N:23]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:24]2(=[O:29])=[O:28])=[N:42][C:41]=1[CH3:46])=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=S1(=O)NCCN1Cc1ccccc1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Agent: N#CN=C1NCCN1Cc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccccc3)S2(=O)=O)sc1C(=O)NCc1ccccc1
Yield: 78 %

Procedure:
Following the procedure as described in Example 27, making variations as required to replace N-(1-benzylimidazolidin-2-ylidene)cyanamide with 2-benzyl-1,2,5-thiadiazolidine 1,1-dioxide to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 78% yield: mp 135-137° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.37-7.26 (m, 10H), 5.99 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 4.25 (s, 2H), 4.00 (t, J=6.6 Hz, 2H), 3.39 (t, J=6.6 Hz, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.5, 156.6, 153.4, 137.7, 133.7, 128.9, 128.8, 128.6, 127.8, 127.7, 119.4, 51.4, 45.0, 44.1, 43.9, 17.3; MS (ES+) m/z 443.2 (M+1).
Reaction SMILES: [CH3:1]C(C)=O.[CH:5]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.S([O-])(OC)(=O)=O.[OH-].[Na+]>O>[CH3:1][N:16]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:17]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC(C)=O
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: COS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c2ccccc2c2ccccc21

Procedure:
The 9-substituted lower alkyl carbazoles are obtained in almost quantitative yield by the action of a concentrated aqueous solution of sodium or potassium hydroxide upon an acetone solution of carbazole using an appropriate lower alkyl iodide or sulfate. Thus, for example, when an acetone solution of carbazole and methyl sulfate is mixed with an aqueous solution of sodium hydroxide, vigorously shaken and poured into water, an almost quantitative yield of N-methylcarbazole is obtained.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:18][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.[C:19]1(O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:1]([CH2:2][C@H:3]1[CH2:18][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccccc1
Reactant: OC[C@@H]1CC[C@H]2CN(c3ncccn3)CCN2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(OC[C@@H]2CC[C@H]3CN(c4ncccn4)CCN3C2)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
A solution of 0.385 g (1.55 mmol) of (7R,9aS)-7-hydroxymethyl-2-(pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 4), 0.220 g (2.34 mmol) of phenol, and 0.488 g (1.86 mmol) of triphenylphosphine in 30 mL of dry THF was treated with 0.324 g (1.86 mmol) of diethyl azodicarboxylate, and the mixture stirred at 23° C. for 16 h. The solvent was evaporated, the residue dissolved in ethyl ether and treated with HCl(g) in ether. The precipitate was collected on a Buchner funnel, and washed with 1:1 ether:ethyl acetate three times. The solid was dissolved in water, basified with 1M NaOH and extracted with chloroform. The organic layer was washed with 1M NaOH (2×) and water (1×), dried (magnesium sulfate), filtered and evaporated to give 0.310 g of (7R,9aS)-7-phenoxymethyl-2,3,4,6,7,8,9,9a-octahydro-2-pyrimidin-2-yl-1H-pyrido[1,2-a]pyrazine. mp (.HCl) 203°-205° C. 13C NMR (base, CDCl3): δ 27.0, 29.0, 36.4, 43.6, 49.1, 54.9, 58.8, 60.8, 70.9, 109.8, 114.5, 120.6, 129.4, 157.7, 159.0, 161.5. HRMS calcd for C19H24N4O: 324.195. Found: 324.194.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].C(OC)(C)(C)C>C(O)(C)C>[ClH:10].[C:1]1([CH:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N)c1ccccc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: CC(N)c1ccccc1
Temperature: 0 °C
Yield: 84.4 %

Procedure:
At room temperature 122 g of (R)-1-phenylethylamine (1.0 mol) was dissolved in 30 mL of isopropanol. The solution was stirred and cooled to 0° C. Then, a previously prepared solution of 100 mL of 37% hydrochloric acid (118 g, 1.2 mol) in 320 mL of isopropanol was added during 1 h. The solution was stirred at 0° C. for an additional 40 min, and then it was concentrated on a rotary evaporator (16 mbar, bath 45° C.) to a volume of 300 mL. The translucent gel which had formed was transferred into a 1.5 l flask, then, under stirring, 250 mL of tert-butyl-methyl-ether was slowly added. Crystals started to form and the suspension was stirred at 0° C. for 3 h. The product was collected by filtration, washed with 100 mL of tert-butyl-methyl-ether and dried at 30° C./16 mbar for 4 hours to give 133 g (84%) of 1-phenylethylamine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17](Cl)=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:20]1([NH:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:37](=[O:40])([O-])O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH2:28][CH2:27][N:26]([C:37](=[O:40])/[CH:16]=[CH:15]/[CH:14]=[CH:13]/[C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: O=C([O-])O
Reactant: COc1cc(/C=C/C=C/C(=O)Cl)cc(OC)c1OC
Reactant: c1ccc(NCCCNc2ccccc2)cc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(/C=C/C=C/C(=O)N(CCCN(C(=O)/C=C/C=C/c2cc(OC)c(OC)c(OC)c2)c2ccccc2)c2ccccc2)cc(OC)c1OC
Yield: 59 %

Procedure:
A solution of 5-(3,4,5-trimethoxyphenyl)penta-(2E, 4E)-dienoyl chloride in methylene chloride (3 ml) was added dropwise to a solution of 68 mg (0.30 mmol) of N,N′-diphenyl-1,3-diaminopropane in pyridine (3 ml) with stirring in an ice bath. After completion of the addition, the mixture was stirred for an additional 1 hour, and a 5% aqueous solution (5 ml) of sodium hydrogencarbonate was added to the reaction mixture to conduct extraction with chloroform. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil (278 mg) was purified by column chromatography on silica gel, thereby obtaining 126 mg (yield: 59%) of the title compound as a colorless amorphous powder.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[C:40]([O:42][CH3:43])=[O:41])=[O:2].[O-:44]Cl=O.[Na+].NS(O)(=O)=O>CC(O)(C)C.O>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[C:40]([O:42][CH3:43])=[O:41])([OH:44])=[O:2]
Reactant: [O-][Cl+][O-]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1Oc1cnccc1C=O)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1Oc1cnccc1C(=O)O)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To a solution of Methyl(1RS,2SR,3RS)-3-[2-[(4-formylpyridin-3-yl)oxy]-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (128 mg, 0.24 mmol) in t-BuOH (10 mL) was added a solution of NaClO2 (34 mg, 0.28 mmol) and NH2SO3H (40 mg, 0.42 mmol) in water (6 mL). The reaction mixture was stirred at room temperature for 2 h and it was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water and brine and dried (Mg2SO4). The solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, 25% ethyl acetate/hexanes containing 5% of acetic acid) to afford the title compound (90 mg, 69%).