Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:13](=O)C1C=CC=CC=1.CI>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH:12][CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: CI
Product: CNCc1ccc(OC)c(OC)c1
Yield: 63.7 %

Procedure:
3,4-Dimethoxybenzenemethanamine (100 g) was mixed with benzaldehyde (64 g), and rotoevaporated to give an oil. Methyl iodide (75 ml) was then added and the mixture was heated for 48 h at 40° and then boiled with 80% ethanol (800 ml) for 3 h. After half of the ethanol had evaporated, the solution was treated with ether (1 liter) to give a solid that was filtered, washed with ether, treated with dilute sodium hydroxide and extracted with ether to give the title compound (69 g) as an oil that was distilled under reduced pressure, b.p. 0.03 mm; 91°.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:33](=[O:49])[N:34]([CH2:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)[CH2:35][CH2:36][CH3:37])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][F:32])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:33](=[O:49])[N:34]([CH2:38][CH2:39][CH2:40][OH:41])[CH2:35][CH2:36][CH3:37])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][F:32])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCF)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CCCO)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCF)cc3)cc2N=C(N)C1
Reaction time: 1 h
Yield: 35 %

Procedure:
2-Fluoroethyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded 0.012 g (35%) of 2-fluoroethyl 2-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate. 1H NMR (400 MHz, CDCl3) δ 7.60-7.65 (m, 2H), 7.49-7.51 (m, 1H), 7.29-7.39 (m, 4H), 6.87 (s, 1H), 4.66-4.69 (m, 1H), 4.54-4.58 (m, 1H), 4.39-4.43 (m, 1H), 4.32-4.36 (m, 1H), 3.73 (s, 2H), 3.58-3.68 (m, 4H), 3.43-3.52 (m, 2H), 1.78-1.87 (m, 2H), 1.65-1.75 (m, 2H), 0.90-0.96 (m, 3H); m/z (APCI-pos) M+1=482.2.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:27]=[CH:26][C:24]([NH:25][CH:2]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]3)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Oc3ccc(Cl)cc3)cc2)CC1
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
In a similar manner as described above in Paragraph A, a solution of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (1 g, 4.5 mmol) and 4-(4-chlorophenoxy)aniline (1 g, 5 mmol) in dichloromethane was stirred as acetic acid (0.39 g, 6.5 mmol) was added. After 15 minutes, sodium triacetoxyborohydride (2 g, 9.4 mmol) was added and the reaction was stirred for 3 days. The reaction was treated with aqueous sodium bicarbonate. The organic layer was washed with water, dried, and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexane gave 1.3 g of 1,1-dimethylethyl 4-[[4-(4-chlorophenoxy)phenyl]amino]-1-piperidinecarboxylate.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[NH2:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[N:10]=1.[CH:19]1([C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[NH2:31])=[O:23])[CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH:19]1([C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[NH:31][S:2]([NH:5][C:6]([NH:8][C:9]2[N:10]=[C:11]([O:17][CH3:18])[CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)=[O:7])(=[O:4])=[O:3])=[O:23])[CH2:20][CH2:21]1
Reactant: COc1cc(OC)nc(N)n1
Reactant: Nc1ccc(F)cc1C(=O)C1CC1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Nc2ccc(F)cc2C(=O)C2CC2)n1
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Chlorosulfonyl isocyanate (2.0 mL, 3.25 g, 23.0 mmol) is added to a solution of 2-amino-4,6-dimethoxypyrimidine (4.13 g, 26.6 mmol) in methylene chloride at 0° C. The resulting mixture is stirred for 30 minutes and a solution of 2-amino-5-fluorophenyl cyclopropyl ketone (4.77 g, 26.6 mmol) and triethylamine (6.3 mL, 4.57 g, 45.2 mmol) in methylene chloride is slowly added to the mixture. The resulting solution is stirred at room temperature for 18 hours, concentrated in vacuo and dissolved in methanol. The methanol solution is adjusted to about pH 1 with 10% hydrochloric acid and extracted with methylene chloride. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and 30% to 50% ethyl acetate in hexanes solutions affords a residue which is crystallized from an ether/petroleum ether solution to give the title product as a pale yellow solid (2.83 g, 24%, mp 76°-78° C.).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[C:17]([Zn]C#N)#[N:18]>CN(C=O)C.O.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>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:5][CH:4]=[N:3][C:2]=2[C:17]#[N:18])=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2ocnc2Br)cc1
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncoc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 240.6 %

Procedure:
A mixture of Example 56B (500 mg, 1.71 mmol), dicyanozinc (221 mg, 1.88 mmol), and Pd(Ph3P)4 (101 mg, 0.087 mmol) in DMF (3 mL) was heated in a microwave reactor to 160° C. for 6 min. The reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with EtOAc. The combined organic extracts were filtered through celite, and the filtrate was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. An identical reaction was then performed using Example 56B (1.0 g, 3.4 mmol), dicyanozinc (442 mg, 3.77 mmol), and Pd(Ph3P)4 (198 mg, 0.171 mmol) in DMF (6 mL). The crude product from both reactions was combined and purified by chromatography on silica gel (25% EtOAc/hexanes) to afford 980 mg (80%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.10 (dd, J=8.9, 0.7, 2H), 8.00 (s, 1H), 7.81 (dd, J=8.7, 0.5, 2H). MS (DCI+) m/z 256 (M+NH4).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH:11]([C:13]([OH:15])=[O:14])[CH3:12])[C:3]1=[O:16].S(Cl)(Cl)=O.[CH2:21](O)[CH3:22].S(Cl)(Cl)=O.[CH2:28]([OH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH2:1][CH:2]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH:11]([C:13]([O:15][CH2:21][CH3:22])=[O:14])[CH3:12])[C:3]1=[O:16].[NH2:1][CH:2]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH:11]([C:13]([O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:14])[CH3:12])[C:3]1=[O:16]
Reactant: OCc1ccccc1
Reactant: CCO
Reactant: CC(C(=O)O)N1CCCCCCC(N)C1=O
Solvent: O=S(Cl)Cl
Product: CC(C(=O)OCc1ccccc1)N1CCCCCCC(N)C1=O
Product: CCOC(=O)C(C)N1CCCCCCC(N)C1=O

Procedure:
Reaction of 3-amino-1-(1-carboxyethyl)- perhydroazonin-2-one (Isomer A, Example 2) with thionyl chloride-ethanol or thionyl chloride-benzyl alcohol followed by concentration and liberation of the free amino ester affords 3-amino-1-(1-ethoxycarbonylethyl)perhydroazonin-2-one and 3-amino-1-(1-benzyloxycarbonylethyl)perhydroazonin-2-one, respectively.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([Br:14])[CH3:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[Br-:14].[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([P+:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(Br)c1ccc2c(c1)C(C)(C)CCO2
Solvent: Cc1ccccc1C
Product: CC(c1ccc2c(c1)C(C)(C)CCO2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 100 °C
Yield: 38.5 %

Procedure:
4.6 g of 4,4-dimethyl-6-(1-bromoethyl)chromane were dissolved in 40 ml of xylene and the solution was treated with 5.3 g of triphenylphosphine. The mixture was heated to 100° C. overnight, cooled, the precipitated crystals were filtered off under suction and washed with hexane. For the further purification, the phosphonium salt was dissolved in methylene chloride and precipitated again by the addition of ethyl acetate. There were obtained 3.5 g of [1-(4,4-dimethyl-6-chromanyl)ethyl]triphenylphosphonium bromide in the form of colorless crystals of melting point 142°-148° C.
Reaction SMILES: [CH:1]1([C:7]2[N:8]3[C:36]4[CH:35]=[C:34]([C:37]([O:39]C)=[O:38])[CH:33]=[CH:32][C:31]=4[CH2:30][CH:9]3[C:10]3[C:22](=O)[CH:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH2:20][C:19](=O)[C:11]=3[CH2:12][N:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(C)C.[OH-].[Na+]>C1COCC1>[CH:1]1([C:7]2[N:8]3[C:36]4[CH:35]=[C:34]([C:37]([OH:39])=[O:38])[CH:33]=[CH:32][C:31]=4[CH2:30][CH:9]3[C:10]3[CH2:22][CH:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH2:20][CH2:19][C:11]=3[CH2:12][N:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)N1C(C3CCCCC3)=C3C=NC=CN3CC3=C(C(=O)C(CCN(C)C)CC3=O)C1C2
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: C1CCOC1
Product: CN(C)CCC1CCC2=C(C1)C1Cc3ccc(C(=O)O)cc3N1C(C1CCCCC1)=C1C=NC=CN1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
To a solution of methyl 11-cyclohexyl-2-[2-(dimethylamino)ethyl]-1,4-dioxo -1,2,3,4,17,17a-hexahydro-6H-indolo[2,1-a]pyrazino[2,1-d][2,5]benzodiazocine-14-carboxylate in THF (0.15 M), 20 eq of BH3.Me2S (2 M solution in THF) were added and the mixture was stirred overnight at RT. The solution was carefully quenched by adding 1.25 N HCl in MeOH until effervescence subsided. Then the volatiles were driven off by boiling the mixture to dryness. The crude residue was dissolved in MeOH (0.06 M) and 10 eq of 1N NaOH (aq) were added. The solution was stirred at 60° C. for 5 h. The solvent was evaporated in vacuo. The crude was then purified by prep RP-HPLC (stationary phase: column WATERS X-TERRA prep. C18, 5 microns. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (8% yield from dimethyl 14-cyclohexyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-7,11-dicarboxylate). 1H NMR (400 MHz, DMSO-d6+TFA, 330 K) δ 8.15 (s, 1H), 7.93 (d, J 8.4, 1H), 7.90-7.85 (m, 1H), 7.76 (d, J 8.4, 1H), 7.70-7.60 (m, 2H), 7.59-7.49 (m, 1H), 4.50-4.40 (m, 1H), 4.30-4.20 (m, 1H), 4.00-3.80 (m, 2H), 3.80-3.70 (m, 1H), 3.70-3.50 (m, 2H), 3.40-3.20 (m, 5H), 2.79 (s, 6H), 2.80-2.70 (m, 2H), 2.70-2.60 (m, 2H), 2.00-1.80 (m, 3H), 1.80-1.60 (m, 2H), 1.60-1.50 (m, 1H), 1.40-1.10 (m, 4H); MS (ES+) m/z 501 (M+H)+.
Reaction SMILES: ClCCN(C1C=CC(N=C=O)=CC=1)CCCl.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.[NH:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][N:27]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[CH2:31][CH2:32][OH:33]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCCNCCO
Agent: O=C=Nc1ccc(N(CCCl)CCCl)cc1
Product: O=[N+]([O-])c1ccc(N(CCO)CCO)cc1

Procedure:
The known compound phenylisocyanate N-mustard 19 can be prepared by following the literature procedure35,36 with modification (Scheme 3). The commercially available 4-fluoronitrobenzene (15) is reacted with diethanolamine under refluxing to give 4-[N,N-bis(2-hydroxyethyl)amino]nitrobenzene (16), which is then converted to 4-[N,N-bis(2-chloroethyl)amino]nitrobenzene (17) by treating with thionyl chloride. Catalytic hydrogenation (10% Pd/C, H2) of compound 17 in ethyl acetate affords N,N-bis(2-chloroethyl)benzene-1,4-diamine (18), which is immediately treated with HCl in ethyl acetate to yield hydrochloride salt of 18. The hydrochloride salt 18 is suspended in CHCl3 and cooled in an ice-bath. To the suspension is added triethylamine and stirred in Argon atmosphere for 5 to 10 min. and then is added dropwise triphosgene solution in CHCl3 and continuously stirred for 20 min. The reaction mixture is evaporated under reduced pressure and the residue is the triturated with THF, filtered and the filtrate containing phenylisocyanate 19, which is used directly for the next reaction without purification. Compound 18 and 19 can be used for the synthesis of the newly invented compounds.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2].CCl.[C:20]([CH:22]([OH:36])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=1)#[N:21].N1C=CC=CC=1>C(Cl)Cl>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)[C:5]([O:36][CH:22]([C:20]#[N:21])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:24]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)F)cc1
Agent: CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(OC(F)F)cc1
Yield: 24.8 %

Procedure:
A solution of α-isopropyl-4-difluoromethoxyphenylacetyl chloride (4.82 g) in methylene chloride (10 ml) is added to a methyl chloride solution (10 ml) of α-cyano-m-phenoxybenzyl alcohol (4.05 g) and pyridine (1.5 ml). The mixture is stirred over the weekend and filtered. The filtrate and the washings are evaporated and the residual oil (6.29 g) is purified on a silica column using 1:1 methylenechloride-hexane as eluent. The solvent was evaporated and the residue treated with sodium borohydride and the resulting product purified on a silica gel column to give 2.01 g of product.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:18]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[CH:34]=O)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[C:36]([CH:41]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:38][CH2:39][CH3:40])=[O:37]>O1CCCC1>[CH2:4]([O:3][C:1]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=[CH:41][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1.[CH2:21]([O:20][C:18]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[CH:34]=[CH:41][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCCN1C(=O)OCc1ccccc1
Reactant: O=CC1CCCCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=CC1CCCCN1C(=O)OCc1ccccc1
Product: CCOC(=O)C=CC1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-carbobenzyloxypyrrolidine-2-carboxaldehyde or N-carbobenzyloxypiperidine-2-carboxaldehyde (5.00 mmol) [S. Kiyooka, et al., J. Org. Chem., 5409 (1989) and y. Hamada, et al., Chem. Pharm. Bull., 1921 (1982)] in anhydrous tetrahydrofuran at -78° C. was added (carbethoxymethylene)triphenylphosphorane (2.09 g, 6.00 mmol. 1.2 eq) as a solid portionwise. The resulting reaction mixture was stirred at room temperature under nitrogen for 2 hours, and then heated at reflux under nitrogen for 1 hour. The reaction mixture was evaporated under reduced pressure and the residue was column chromatographed using silica gel (approximately 100 g) and elution with 20% diethyl ether in hexanes afforded either ethyl 3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate or ethyl 3-(N-benzyloxycarbonylpiperid-2-yl)-2-propenoate.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:33]2[S:34][C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[S:34][C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2sc(N3CCNCC3)nc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4s3)CC2)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A suspension of 0.2 g (0.469 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide, 0.17 g (0.775 mmol) of 2-(piperazin-1-yl)-benzothiazole, 0.1 g of potassium carbonate and 1 ml of water in 10 ml of acetonitrile is stirred for 10 hours at ambient temperature. The reaction mixture is then poured onto water, extracted with dichloromethane and the organic phase is dried over sodium sulphate. The product is purified by column chromatography on silica gel (eluant: dichloromethane/acetone =20:1, then dichloromethane/methanol=20:1).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([NH2:13])[CH:11]=[CH2:12].C(N(C(C)C)CC)(C)C>C(O)C>[CH2:10]([NH:13][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)[CH:11]=[CH2:12]
Reactant: C=CCN
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C=CCNc1nc(Cl)ncc1Br
Yield: 89 %

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (5.0 g, 22 mmol), allylamine (1.98 mL, 26.4 mmol), and diisopropylethylamine (5.6 mL, 33.0 mmol) are stirred in ethanol (100 mL) at 50° C. overnight. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer is washed with brine, dried over anhydrous sodium sulfate and evaporated to provide Allyl-(5-bromo-2-chloro-pyrimidin-4-yl)-amine as a white crystalline solid (89%), which is used without further purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH:8]([NH:10][C:11]([C:13]2[C:14]([CH:19]([F:21])[F:20])=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:12])[CH3:9])=[C:4]([Cl:22])[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+].C(COC)OC>O.C(OC(=O)C)C>[Cl:22][C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[S:6][C:5]=1[CH2:7][CH:8]([NH:10][C:11]([C:13]1[C:14]([CH:19]([F:21])[F:20])=[N:15][N:16]([CH3:18])[CH:17]=1)=[O:12])[CH3:9]
Reactant: CC(Cc1sc(Br)cc1Cl)NC(=O)c1cn(C)nc1C(F)F
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(Cc1sc(-c2ccc(F)cc2)cc1Cl)NC(=O)c1cn(C)nc1C(F)F

Procedure:
In a sulfonation flask a mixture containing of 207 mg (0.5 mmol) 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid[2-(5-bromo-3-chlorothiophen-2-yl)-1-methylethyl]amide, 90 mg (0.64 mmol) 4-fluorophenylboronic acid, 151 mg (1.8 mmol) sodiumbicarbonate, 36 mg (0.05 mmol) bistriphenylphosphine palladium dichloride, 10 ml dimethoxyethane and 5 ml of water is stirred at reflux for 6 hours. After cooling to ambient temperature ethylacetate and water is added and the organic layer separated and washed again twice with water. After drying (sodium sulphate) and distilling off the solvent in a water jet vacuum, the crude product is obtained. Purification is achieved by column chroma-tography over silicagel (eluent: ethylacetate/heptane 1:1). Yield: 180 mg (80% of theory) of a slightly brown oil (1H-NMR: 1.29/d/3H, 0.9/m/2H, 3.09/m/2H, 3.89/s/3H, 4.42/m/1H, 6.38/s (broad)/1H, 6.89/t/1H—CF2H, 7.05/m/2H, 7.48/m/2H, 7.89/s/1H).
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:7]=1)=[O:5])C.[CH2:17]([CH:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21].C([Al](CC)CC)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:17]([CH:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)[N:7]=2)=[O:5])[CH2:26][CH2:27]1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)c1nc(-c2ccncc2)no1
Reactant: CCCCCC1CCC(N)CC1
Agent: CC[Al](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCC1CCC(NC(=O)c2nc(-c3ccncc3)no2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-pyridin-4-yl-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (50.5 mg, 0.23 mmol) and 4-pentylcyclohexylamine (39 mg, 0.23 mmol) in anhydrous toluene (2 ml) was treated with triethylaluminium (345 μl of a 2M solution in hexanes, 0.69 mmol). After stirring at rt for 18 h, saturated aqueous NaHCO3 (2 ml) was added and the mixture diluted with CH2Cl2 (25 ml). The organic phase was separated, washed with brine (5 ml) and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to afford the title compound: RT=4.14 min; m/z (ES+)=343.2 [M+]+.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][C:5]=1[CH3:11].[C:12](=[O:15])([O-])[O-].[K+].[K+].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CC(C)=O.C(Cl)(Cl)(Cl)Cl>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:15][CH3:12])=[CH:6][C:5]=1[CH2:11][Br:18]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(O)ccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CI
Product: COc1ccc(Cl)c(CBr)c1
Reaction time: 1.5 h

Procedure:
Methyl iodide (110 g was added dropwise to a stirred solution of 4-chloro-3-methylphenol (100 g) and potassium carbonate (194 g) in acetone (500 ml). The mixture was stirred for 1.5 hours. Methyl iodide (142 g) was added and the mixture stirred for a further hour. Solvent was removed by evaporation and the residue partitioned between water and ethyl acetate. The organic layer yielded an oil which was heated under reflux for 2 hours with N-bromosuccinimide (119 g) and benzoyl peroxide (1 g) in carbon tetrachloride (250 ml). The mixture was cooled, filtered and the filtrate concentrated to give a residue which was distilled under high vacuum. The fractions collected between 88° and 94° C./0.4 mbar were recrystallised from petroleum ether (b.p. 60°-80° C.) to give 2-chloro-5-methoxy benzyl bromide, m.p. 51°-52° C.