Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N+:11]([O-:15])=[CH:10][C:9]=1[Cl:16])=[O:4].[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][S:42](Cl)(=[O:44])=[O:43])=[CH:37][CH:36]=1)([O-:34])=[O:33]>N1C=CC=CC=1.CCOC(C)=O>[Cl:16][C:9]1[CH:10]=[N+:11]([O-:15])[CH:12]=[C:13]([Cl:14])[C:8]=1[CH2:7][C@@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[O:5][C:3](=[O:4])[CH2:2][NH:1][S:42]([CH2:41][C:38]1[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=1)(=[O:43])=[O:44]
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Reactant: NCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(CNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-4-(2-(2-aminoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (prepared in an analogous manner to that described in Scheme 1, Step 1-2) (243 mg, 0.509 mmol) dissolved in pyridine (1 mL), cooled at 0° C., (4-nitrophenyl)methanesulfonyl chloride (100 mg, 0.424 mmol) was added. The mixture was stirred at 0° C. for 2 hours. The mixture was then diluted with EtOAc and washed with HCl 0.1N, NaHCO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and the solvent was evaporated. (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-((4-nitrophenyl)methyl-sulfonamido)acetoxy)ethyl)pyridine 1-oxide was obtained (287 mg, 0.42 mmol, quantitative yield).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:13]3[CH2:17][CH:16]4[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH:15]4[CH2:14]3)[CH:9]=2)[N:4]=[CH:3]1.FC(F)(F)C(O)=O>ClCCl.CO>[CH2:14]1[CH:15]2[CH2:20][NH:19][CH2:18][CH:16]2[CH2:17][N:13]1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[CH:3][N:2]([CH3:1])[C:11]2=[O:12]
Reactant: Cn1cnc2ccc(N3CC4CN(C(=O)OC(C)(C)C)CC4C3)cc2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cn1cnc2ccc(N3CC4CNCC4C3)cc2c1=O
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of tert-butyl 5-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (Intermediate 20A) (80 mg, 0.22 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL) and the reaction allowed to stand overnight. The reaction was diluted with methanol and passed through a scx cartridge (500 mg) to afford 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-methylquinazolin-4(3H)-one (58 mg, 0.21 mmol).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=3)[CH:19]=2)[CH2:14]1.CCN(CC)CC>C(Cl)Cl>[CH:12]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=3)[CH:19]=2)[CH2:14]1)=[O:11]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CC(CO)C3)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CC(C=O)C3)nc1
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
Combine DCM (3 mL) and oxalyl chloride (41 uL) under nitrogen atmosphere at −78° C., and then add DMSO (49 uL) in DCM (2 mL). After the solution stirs for 15 minutes, add 6-(2-Hydroxymethyl-indan-5-yloxy)nicotinamide (33.1 mg, 0.116 mmol) in DCM (2 mL). After 15 minutes, add Et3N (97 uL, 0.70 mmol). After the reaction gradually warms to room temperature over the next 5 hours, then quench with water. Add the mixture to a separatory funnel and extract the product with DCM. Wash the organic phase with brine and then dry over Na2SO4. After concentrating under reduced pressure, flash chromatograph using 10% THF/CH2Cl2 eluent affords 27.4 mg, 0.10 mmol (84% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 3.1-3.2 (2H, m), 3.2-3.4 (3H, m), 6.8-7.0 (4H, m), 7.1-7.3 (1H, m), 8.8-8.9 (1H, m), 8.4 (1H, s), 9.7 (1H, s); TLC 1:6 THF:CH2Cl2Rf:=0.7.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C@H:5]([CH2:9][OH:10])[CH2:6][CH:7]=[CH2:8].[CH3:19][C:20]1C=CC(S(O)(=O)=O)=C[CH:25]=1.COC(OC)(C)C>CC(C)=O>[OH:10][CH2:9][C@H:5]([CH2:6][CH:7]=[CH2:8])[CH2:4][C@H:3]1[CH2:2][O:1][C:20]([CH3:25])([CH3:19])[N:11]1[C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18]
Reactant: C=CC[C@@H](CO)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Product: C=CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -20 °C
Yield: 956.1 %

Procedure:
To a solution of tert-butyl (2S,4R)-1-hydroxy-4-(hydroxymethyl)hept-6-en-2-ylcarbamate (6.8 g, 26.2 mmol) in acetone (150 mL), PTSA (0.45 g, 2.62 mmol) was added. The reaction mixture was cooled to −20° C. followed by the addition of 2,2-dimethoxypropane (4.1 g, 39.4 mmol). The resulting mixture was stirred and allowed to warm to rt for 1 hr. TEA (0.5 mL) was then added and stirred for another 5 min. The solvent was removed under reduced pressure. The residue was dissolved in Et2O (300 mL), washed with 1 N HCl (80 mL), sat. aq. NaHCO3 (80 mL), brine (80 mL) successively, and dried, filtered, and concentrated under vacuum to give crude (S)-tert-butyl 4-((R)-2-(hydroxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (7.5 g, 96%). It was used without further purification.
Reaction SMILES: [B:1]([F:4])([F:3])[F:2].[F:5][H-]F.[F:8][N+:9]([F:12])([F:11])[F:10].F>>[F:2][B-:1]([F:8])([F:4])[F:3].[F:8][N+:9]([F:12])([F:11])[F:10].[FH:5]
Reactant: FB(F)F
Reactant: F[H-]F
Agent: F
Agent: F[N+](F)(F)F
Product: F[B-](F)(F)F

Procedure:
adding boron trifluoride to the separated solution of tetrafluorammonium bifluoride in anhydrous liquid hydrogen fluoride to form tetrafluorammonium tetrafluoroborate in solution with hydrogen fluoride;
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]=[C:7]1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][C:20]=1[F:26])C.[CH3:28][C:29]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=3)=[CH:46][CH:45]=2)[CH2:38][CH2:37]1)([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:77][P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:20]1[C:21]([F:77])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][C:7]1[N:6]([CH2:5][C:4]([N:42]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:51]=[CH:52][C:53]([C:56]([F:58])([F:57])[F:59])=[CH:54][CH:55]=3)=[CH:46][CH:45]=2)[CH:39]2[CH2:38][CH2:37][N:36]([C:29]([CH3:28])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:41][CH2:40]2)=[O:3])[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]=1
Reactant: F[P-](F)(F)(F)(F)F
Reactant: CCOC(=O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2cccnc21
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.5 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C1) (115 mg, 1 equiv), ethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B2) (150 mg, 1 equiv), HATU (151 mg, 1.2 equiv), DMF (2.7 ml) and DIPEA (0.17 ml, 3 equiv) was shaken at room temperature for 5 h. The reaction mixture was partitioned between ethyl acetate/methanol and aqueous sodium bicarbonate, then the organic layer was brine-washed and dried. Flash chromatography (silica, 3-4% methanol in DCM) gave ethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate as a white solid (190 mg).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:12]([C:18]([C:20]([F:23])([F:22])[F:21])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH:1]1([NH:7][C:8]2[O:9][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([C:20]([F:21])([F:23])[F:22])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: NC(=O)NC1CCCCC1
Product: CCOC(=O)c1oc(NC2CCCCC2)nc1C(F)(F)F
Yield: 38.7 %

Procedure:
By the procedure of Example 4, 8.52 g (60 mmol) of cyclohexyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 72 hours. The product was separated and then recrystallized several times from methylcyclohexane to yield 5.92 g of a fine white powder product (m.p.=73°-74° C.) identified in Table I.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1.[C:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([OH:36])=O)=[N:32][CH:33]=2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20].[CH3:37]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:16][CH2:15][C:12]3[CH:13]=[C:14]([CH3:37])[C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=4)=[N:10][CH:11]=3)=[O:36])=[N:32][CH:33]=2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(=O)N1CCN(c2ccc(C(=O)O)nc2)CC1
Reactant: NCc1ccc(-c2ccnc(C(F)(F)F)c2)nc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(C)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methanamine 48-1 (27 mg, 0.10 mmol), 5-(4-acetylpiperazin-1-yl)picolinic acid 48-2 (25 mg, 0.10 mmol) and HATU (38 mg, 0.10 mmol) in DMF (0.6 mL) was added DIEA (0.08 mL, 0.50 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 5-(4-acetylpiperazin-1-yl)-N-((3-methyl-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methyl)picolinamide 48 as a white powder. MS m/z 499.20 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.20 (t, 1H, J=6.4 Hz), 8.86 (d, 1H, J=5.2 Hz), 8.53 (m, 1H), 8.32 (d, 1H, J=2.8 Hz), 8.04 (s, 1H), 7.93-7.86 (m, 2H), 7.72 (m, 1H), 7.43 (dd, 1H, J1=8.8 Hz, J2=2.8 Hz), 4.52 (d, 2H, J=6.4 Hz), 3.60-3.58 (m, 4H), 3.41-3.38 (m, 4H), 2.36 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[NH:10]([CH2:12][CH2:13][OH:14])[NH2:11].Cl>C(O)C.O.C(OCC)(=O)C>[NH2:6][C:5]1[N:10]([CH2:12][CH2:13][OH:14])[N:11]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNCCO
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(N)n(CCO)n1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of 4,4-dimethyl-3-oxo-pentanenitrile (5.0 g, 0.04 mol) in absolute ethanol (50 mL), add 2-hydrazino-ethanol (3 mL, 1.1 equiv.) and concentrated HCl (0.5 mL). Reflux the reaction for 4 hours then cool to room temperature and dilute with water and ethyl acetate. Wash the organics with water then saturated aqueous saturated sodium chloride then dry with magnesium sulfate, filter and concentrate in vacuo. Trituration from hexanes and dichloromethane gives a white solid (4.8 g, 66%). MS (ES), m/z 184 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:20]O>Cl.O1CCOCC1>[CH3:20][O:18][C:17](=[O:19])[CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)[CH:11]=1
Reactant: O=C(O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A mixture of [3-(1H-indol-4-yl)-phenyl]-acetic acid (4 g, 15.9 mmol), 4N HCl (20 drops) in methanol (30 mL) and dioxane was stirred at rt for 4 hours. The reaction was concentrated, diluted in ethyl acetate, washed with NaHCO3 (2×), brine (2×), dried and concentrated to give 3.72 g (88%) of [3-(1H-Indol-4-yl)phenyl]-acetic acid methyl ester. General Procedure for the Syntheses of the Precursor, 4-Aryl-1,3-dihydro-indol 2-one
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([N:19]3[C:38]4[C:26](=[CH:27][C:28]5[C:29]([CH3:46])([CH3:45])[C:30]6[CH:31]=[C:32]([C:39]7[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=7)[CH:33]=[CH:34][C:35]=6[C:36]=5[CH:37]=4)[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:54])C(=O)C1.O>C(#N)C>[Br:54][C:23]1[CH:24]=[C:25]2[C:20]([N:19]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=3)[C:38]3[C:26]2=[CH:27][C:28]2[C:29]([CH3:46])([CH3:45])[C:30]4[CH:31]=[C:32]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH:33]=[CH:34][C:35]=4[C:36]=2[CH:37]=3)=[CH:21][CH:22]=1
Reactant: CC1(C)c2cc(-c3ccccc3)ccc2-c2cc3c(cc21)c1ccccc1n3-c1nc(-c2ccccc2)cc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: CC1(C)c2cc(-c3ccccc3)ccc2-c2cc3c(cc21)c1cc(Br)ccc1n3-c1nc(-c2ccccc2)cc(-c2ccccc2)n1
Reaction time: 4 h

Procedure:
138 g (234.6 mmol) of 6-(4,6-diphenylpyrimidin-2-yl)-12,12-dimethyl-2-phenyl-6,12-dihydro-6-azaindeno[1,2-b]fluorene are initially introduced in 1000 ml of acetonitrile. A solution of 41.7 g (234.6 mmol) of NBS in 500 ml of CH3 CN is subsequently added dropwise at −15° C. with exclusion of light, and the mixture is allowed to come to room temperature and is stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2 Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane and filtered off with suction.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:17][CH:16]=2)[C:10]([NH:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:36][C:37]1[S:41][CH:40]=[N:39][CH:38]=1>C(#N)C.CCOCC>[Br-:1].[CH3:36][C:37]1[S:41][CH:40]=[N+:39]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([C:10]([NH:12][CH3:13])=[O:11])[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:17][CH:16]=3)[CH:4]=2)[CH:38]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CN(C(=O)NC)c2cccc(CBr)c2)cc1
Reactant: Cc1cncs1
Solvent: CCOCC
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1ccc(CN(C(=O)NC)c2cccc(C[n+]3csc(C)c3)c2)cc1
Product: [Br-]
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A mixture of 3.3 g of N-[3-(bromomethyl)phenyl]-N'-methyl-N-[[4-(tetradecyloxy)phenyl]methyl]-urea and 2.1 g of 5-methylthiazole in 50 ml of acetonitrile is refluxed under argon for 5 hours. The mixture is allowed to stand at room temperature overnight. The mixture is diluted with ether and the solid collected. The solid is washed several times with ether then vacuum dried to give 3.7 g of the desired product as a white solid, m.p. 124°-126° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:17]1([C:16]([NH:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(OCCN)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCNC(=O)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a suspension of methyl 4-(2-amino-ethoxy)benzoate hydrochloride (0.232 g, 1 mmol) in THF (6 ml) was added benzoyl chloride (0.140 g, 1 mmol) followed by triethylamine (0.121 g, 1.2 mmol). The reaction mixture was stirred for 1 h and then diluted with ethyl acetate. The organic layer was washed with 0.5 M aqueous HCl, saturated sodium bicarbonate solution, and brine. The organic layer was concentrated in vacuo to give methyl 4-(2-benzenecarbonylamino-ethoxy)benzoate which was directly used in the next step.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][C:33]([CH3:36])([CH3:35])[NH2:34])[CH2:23][CH3:24])[CH3:21].C(#N)C>C(OCC)(=O)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][C:33]([NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])([CH3:35])[CH3:36])[CH2:23][CH3:24])[CH3:21]
Reactant: CCN(CC)CC1CCCCN1CC(C)(C)N
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(CC)CC1CCCCN1CC(C)(C)NC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 62 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(diethylamino)methyl]-piperidin-l-yl]-1,1-dimethyl-ethanamine in a yield of 62% of theory. Colourless crystals, m.p. 160°-162° C. (acetonitrile and ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C:17]([C:19]2[S:26][C:25]([CH3:27])=[C:24]3[C:20]=2[CH2:21][C@H:22]2[C:28]([CH3:30])([CH3:29])[C@H:23]23)=[O:18])[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C:17](=[O:18])[C:19]2[S:26][C:25]([CH3:27])=[C:24]3[C:20]=2[CH2:21][C@H:22]2[C:28]([CH3:30])([CH3:29])[C@H:23]23)[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][S:41]([CH3:40])(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1OCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 471.3 %

Procedure:
To a solution of 3-[3-chloro-4-(3-hydroxy-propoxy)-5-methoxy-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (430 mg, 0.958 mmol) in DCM (20 mL) and DIPEA (0.262 mL, 1.53 mmol) is added methane sulfonylchloride (0.090 mL, 1.15 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 3-{2-chloro-6-methoxy-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-propyl ester (2.38 g) as a brown oil; LC-MS: tR=1.14 min, [M+1]+=527.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[N:15](C(O)=O)[CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[CH:4][CH:3]=1>C(O)(=O)C.O.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH:10]3[NH:15][CH:13]([CH2:12][CH2:11]3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)N1C2C=C(c3ccc(Cl)cc3)CC1CC2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(C2=CC3CCC(C2)N3)cc1
Yield: 81.5 %

Procedure:
Racemic 3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene-8-carboxylic acid #2,2,2-trichloro-ethyl ester (7.5 g, 18.98 mmol) in acetic acid (75 mL) and water (10 mL) was heated at 45° C. Zinc (16.63 g, 257.39 mmol) was added portionwise to the reaction over 1 hour. Mix was filtered through Celite and the filtrate was concentrated to a clear oil. The oil was dissolved in water (100 mL) adjusted to PH=12 with 1N sodium hydroxide and extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with brine (100 mL), dried with magnesium sulfate and concentrated to yield racemic 3-(4-Chloro-phenyl)-8-aza-bicyclo[3.2.1]oct-2-ene (3.4 g, 81.5%) as a white solid with had the following properties: Mp 91-93° C.; 1H NMR CDCl3 δ: 7.30-7.21 (m, 4H), 6.41 (d, J=5.6 Hz, 1H), 3.85 (t, J=5.6 Hz, 1H), 3.80 (t, J=5.6 Hzm 1H), 2.80 (d, J=17.2 Hz, 1H), 2.17 (d, J=17.2 Hz, 1H), 2.11-1.69 (m, 3H), 1.66-1.57 (m, 1H). IR (KBr): 3965, 3887, 3721, 3664, 3477, 3304, 3237, 3081, 3048, 3020, 2966, 2928, 2882, 2835, 2710, 2675, 2595, 2495, 2425, 2396, 2362, 2314, 2104, 1967, 1935, 1913, 1894, 1847, 1791, 1707, 1630, 1589, 1563, 1494, 1466, 1446, 1428, 1403, 1380, 1360, 1341, 1307, 1279, 1249, 1239, 1221, 1190, 1151, 1092, 1068, 1030, 1008, 973, 948, 935, 916, 876, 850, 811, 755, 738, 726, 706, 672, 665, 631, 610, 554, 544, 524, 519, 469, 445, 433, 421, (cm−1). Analysis calculated for C13H14ClN.⅓ H2O: C, 69.18; H, 6.55; N, 6.21; Found: C, 69.42; H, 6.36; N, 6.15.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=O.C1CCCCC1.CCOC(C)=O>O1CCCC1>[Br:24][C:20]1[CH:19]=[C:18]([C:16]([C:2]2[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=2)=[CH2:15])[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(Br)cn1
Reactant: CC(=O)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: C=C(c1ccc(OC)nc1)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 5-bromo-2-methoxy-pyridine (10.0 g, 1 eq) in dry tetrahydrofuran (50 ml) was treated dropwise at −78° C. under a nitrogen atmosphere with n-butyllithium (1.6N in hexane, 30 ml, 0.9 eq). The mixture was stirred at −78° C. for 1 hour, then was added a solution of 3-bromo acetophenone (7.7 ml, 1.1 eq) in dry tetrahydrofuran (20 mL) at −78° C. The mixture was then allowed to warm to room temperature. The progress of the reaction was checked by TLC (cyclohexane/AcOEt 9:1). After 1 hour conversion to the desired product was complete. For the workup, saturated solution of ammonium chloride (30 ml) was added, the tetrahydrofuran layer was separated, and then the aqueous phase was extracted with dichloromethane (3×20 ml). The organic fractions were collected, dried over sodium sulphate and evaporated. The crude was dissolved in acetic acid (100 ml) and concentrated sulphuric acid (20 ml) was added, and mixture was stirred at room temperature for 2 hours. A solution of sodium hydroxide (15%) was added to the mixture until pH 6-5, then it was extracted with dichloromethane (3×25 ml). The organic phases were collected, dried and evaporated. The crude was purified by flash chromatography eluting with cyclohexane. 10.3 g of The 5-[1-(3-bromo-phenyl)-vinyl]-2-methoxy-pyridine was obtained as colorless oil (10.3 g, 71% of theory). MS (ISP): m/z=291.9 [M+H]+.