Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[NH2:2].[NH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][C:20]=1[S:28]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])=[O:29].C(N(CC)CC)C.Cl>CN(C)C=O.O>[C:32]([NH:31][S:28]([C:20]1[CH:21]=[C:22]([CH:25]([CH3:26])[CH3:27])[CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][NH:16][S:10]([C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=1[O:14][CH3:15])[C:1]([NH2:2])=[O:3])(=[O:12])=[O:11])(=[O:30])=[O:29])([CH3:33])([CH3:34])[CH3:35]
Reactant: COc1ccc(C(N)=O)cc1S(=O)(=O)Cl
Reactant: CC(C)c1ccc(CCN)c(S(=O)(=O)NC(C)(C)C)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(N)=O)cc1S(=O)(=O)NCCc1ccc(C(C)C)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.3 %

Procedure:
To a suspension of 241 mg of 5-carbamoyl-2-methoxybenzene-sulfonyl chloride and 288 mg of 2-(2-aminoethyl)-N-tert-butyl-5-isopropylbenzenesulfonamide in 10 mL of N,N-dimethyl-formamide was added 0.32 mL of triethylamine, and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added 30 mL of water, and the mixture was stirred at the same temperature for 1 hour. To the mixture was added 10 mL of 1 mol/L hydrochloric acid, and the mixture was extracted three times with 20 mL of ethyl acetate. The organic layers were combined and washed with 30 mL of water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 426 mg of 3-[[2-(2-tert-butylsulfamoyl-4-isopropylpheyl)ethyl]sulfamoyl]-4-methoxybenzamide.
Reaction SMILES: [CH3:1][C:2]([C:5]([OH:7])=[O:6])([CH3:4])[NH2:3].[OH-].[Na+].[C:10](#[N:13])[CH:11]=[CH2:12].C(O)(=O)C>O>[C:10]([CH2:11][CH2:12][NH:3][C:2]([CH3:4])([C:5]([OH:7])=[O:6])[CH3:1])#[N:13]
Reactant: CC(C)(N)C(=O)O
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(NCCC#N)C(=O)O
Reaction time: 8 h
Yield: 96 %

Procedure:
50 g (0.48 mol) of 2-methylalanine were added to a cooled solution (water/ice) of NaOH (19.6 g) in water (100 ml). Once the solution had turned clear, 34 ml (0.50 mol) of acrylonitrile were dropped on cooling. The mixture was left overnight. After 18 hours, 28 ml of acetic acid were added on cooling (water/ice); a white solid precipitated; 200 ml of 95% ethanol were dropped in the flask, stirring was continued for 1 hour, then the mixture was allowed to stand in a fridge for 2-3 hours. After filtration, the solid was collected and dried in an oven at 80° C. The filtrates were evaporated and taken up with ethanol (160 ml). On cooling a further amount of product was obtained, which was filtered and dried. 72 g of the title compound were obtained from the first filtration. Total yield: 95%.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].BrC1C(OC)=C(C(CBr)=CC=1)[C:27](OC)=[O:28].COC1C=C(S)C=CC=1>>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:28][CH3:27])[CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Agent: COc1cccc(S)c1
Product: COC(=O)c1c(CSc2cccc(OC)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 73, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 3-methoxythiophenol.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6].O.Cl>O1CCCC1>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCNC(=O)Nc1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCCC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Nc1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2OCCCC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.9 %

Procedure:
1.3 mL (1.3 mmol) of aqueous 1 N lithium hydroxide solution are added to a solution of 423 mg (0.87 mmol) of methyl (Z)-3-[2-butoxy-3′-(3-heptylureido)biphenyl-4-yl]-2-methoxyacrylate in 10 mL of tetrahydrofuran. The reaction mixture is stirred for 24 hours at room temperature. After addition of 20 mL of water and acidification with 1 N hydrochloric acid, the reaction medium is extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and dried over sodium sulfate. The solvents are evaporated off and the residue is then recrystallized from 5 mL of acetonitrile. 348 mg (85%) of (Z)-3-[2-butoxy-3′-(3-heptylureido)biphenyl-4-yl]-2-methoxyacrylic acid are obtained in the form of a white powder. (m.p.=137° C.).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][C:23]2=O>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH:22]=[C:23]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C1CCCc2c(F)cccc21
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1=CCCc2c(F)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% sodium hydride (5.00 g) in toluene (250 ml) was added dropwise ethyl diethylphosphonoacetate (23.9 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Then, a solution of 5-fluoro-3,4-dihydro-2H-naphthalen-1-one (18.0 g) in toluene (50 ml) was added dropwise, and the mixture was stirred at 80° C. for 3 hr. After cooling to room temperature, the reaction mixture was poured into ice water, and the mixture was extracted with toluene. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give ethyl (5-fluoro-3,4-dihydronaphthalen-1-yl)acetate (17.4 g).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH2:16][CH:15]1[C:18](=[N:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Li]>CCOCC>[CH:1]([N:14]1[CH2:17][CH2:16][CH:15]1[CH:18]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1)C(F)(F)F
Agent: [Li]C
Solvent: CCOCC
Product: O=C(NC(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Cool to 0° C a solution of 1.0 g. of 1-benzhydryl-2-[α-(N-trifluoroacetylimino)benzyl]azetidine (from step A) in 25 ml of ether. To this solution, add 1.3 ml of a 2 molar ethereal solution of methyllithium. Maintain the reaction mixture at 0° C for 1 hour, then allow to stand at room temperature for two hours. Cool the mixture in an ice bath and quench by careful dropwise addition of 45 ml of saturated aqueous ammonium chloride solution. Dilute the mixture with additional ether and water, separate the layers, and wash the organic phase successively with water and saturated aqueous sodium chloride solution. Dry over anhydrous sodium sulfate and remove solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH3:12])=[C:7]([NH2:13])[CH:6]=1)[CH3:2].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:17]=1[CH:18]=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]([CH3:12])[C:18]([C:17]3[C:16]([Cl:15])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:24])=[N:13][C:7]=2[CH:6]=1)=[O:14])[CH3:2]
Reactant: CCOC(=O)c1ccc(NC)c(N)c1
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)nc(-c1c(Cl)cccc1Cl)n2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-amino-4-methylaminobenzoic acid ethyl ester (388 mg) and 2,6-dichlorobenzaldehyde (350 mg) in DMSO (4 mL) was added Yb(OTf)3 (50 mg) and the solution was stirred at room temperature for 24 h. More Yb(OTf)3 was added and stirring was continued for 24 h. This process was repeated another two times. The reaction mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by flash chromatography using a gradient of ethyl acetate/CH2Cl2 (0% to 25%) to give 2-(2,6-dichlorophenyl)-1-methyl-1H-benzoimidazole-5-carboxylic acid ethyl ester as a beige solid, mp=164-166° C.; MS (m/z) 349 (M+1).
Reaction SMILES: [CH:1]1([N:4]([CH:32]2[CH2:34][CH2:33]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:24]=[C:23]([C:25](O)=[O:26])[N:22]([CH3:28])[N:21]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:35][N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:37].F[P-](F)(F)(F)(F)F.CNC.C1COCC1>CN(C=O)C.O>[CH:32]1([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C:7]2[N:29]([CH2:30][CH3:31])[C:10]3=[N:11][C:12]([NH:19][C:20]4[CH:24]=[C:23]([C:25](=[O:26])[N:36]([CH3:37])[CH3:35])[N:22]([CH3:28])[N:21]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:33][CH2:34]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C(=O)O)n(C)n3)nc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3cc(C(=O)N(C)C)n(C)n3)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
A mixture of 3-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-1-methyl-1H-pyrazole-5-carboxylic acid (39.8 mg, 0.086 mmol), HATU (49.0 mg, 0.129 mmol) and dimethylamine, 2M in THF (0.086 mL, 0.172 mmol) in DMF (2 mL) was stirred at room temperature for 2 h. Water was added and the reaction mixture was extracted with ethyl acetate 3 times. The combined organic layers were washed twice with 10% lithium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude was purified by preparative HPLC to give N,N-dicyclopropyl-4-(5-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (23 mg, 54.1% yield) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:23][CH2:24][CH2:25]OS(C)(=O)=O)[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:31]([CH2:25][CH2:24][O:23][CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCOS(C)(=O)=O)c2cccc(F)c2F)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCN=[N+]=[N-])c2cccc(F)c2F)C1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of (3R)-tert-butyl 3-((2,3-difluorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (4.2 g, 9.4 mmol) and solid NaN3 (0.92 g, 14.1 mmol) in anhydrous DMF (30 mL) was heated to 80° C. overnight. The reaction mixture was cooled to rt and diluted with ethyl acetate (80 mL), the organic phase was washed with water (30 mL×3), dried over Na2SO4 and evaporated. The residue was separated on a silica column to give (3R)-tert-butyl 3-((2-azidoethoxy)(2,3-difluorophenyl)methyl)piperidine-1-carboxylate (3.4 g, 92%). 1H NMR (CDCl3, 400 MHz) δ 7.14 (m, 3H), 4.50 (q, 1H), 4.10 (m, 1H), 3.40 (m, 4H), 2.70 (m, 2H), 1.90 (m, 2H), 1.65 (m, 1H), 1.41 (d, 9H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[CH2:17][CH2:16][O:15][C:14]=2[CH:18]=1>C(#N)C>[Br:8][C:11]1[C:10]([Br:9])=[CH:18][C:14]2[O:15][CH2:16][CH2:17][C:13]=2[CH:12]=1
Reactant: Brc1ccc2c(c1)OCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Brc1cc2c(cc1Br)OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NBS (450 mg, 2.53 mmol) was added to a solution of 6-bromo-2,3-dihydrobenzo[b]furan (137) (504 mg, 2.53 mmol) in 15 ml ACN. The reaction mixture was stirred overnight at r.t. The yellow solution was poured into ice-water, extracted with EA. Org. phase was washed with aq. sodium bicarbonate and brine subsequently. After dried over sodium sulfate the org. phase was concentrated to give 676 mg (purity ca. 90%) title compound as dark oil which solidified after standing at r.t.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1/[CH:15]=[CH:16]/[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:12]([Cl:26])[CH:11]=[C:10]([Cl:27])[CH:9]=2)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:38][Si:39]([CH2:42][CH2:43][O:44][CH2:45]Cl)([CH3:41])[CH3:40]>CN(C=O)C.O>[C:19]1([NH:18][C:17](/[CH:16]=[CH:15]/[C:14]2[C:13]3[C:8](=[CH:9][C:10]([Cl:27])=[CH:11][C:12]=3[Cl:26])[N:7]([CH2:45][O:44][CH2:43][CH2:42][Si:39]([CH3:41])([CH3:40])[CH3:38])[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1/C=C/C(=O)Nc1ccccc1
Reactant: C[Si](C)(C)CCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/C(=O)Nc2ccccc2)c2c(Cl)cc(Cl)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a cooled (0°) solution of (E)-Ethyl-3-[2-(phenylcarbamoyl)ethenyl]-4,6-dichloroindole-2-carboxylate (300 mg) in dry DMF (25 ml) a solution of sodium bis-(trimethylsilyl)amide (1M;0.0814 ml) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes then cooled to 0°. Trimethylsilylethoxymethylchloride (185 mg) was added, and the reaction was stirred for one hour at room temperature. The resulting solution was poured in H2O (20 ml) and extracted with diethylether (15 ml×3). The organic layers were dried, concentrated under vacuum and the product isolated by chromatography on silica gel(CH/EA:83/15) to give the title compound (311 mg). Rf =0.35 CH/EA:85/15
Reaction SMILES: C1COCC1.[C:6]1([S:12][CH:13]=[CH:14][C:15](Cl)=[O:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>C(N(CC)CC)C>[CH3:18][C:19]1[CH:20]=[C:21]([NH:22][C:15](=[O:16])[CH:14]=[CH:13][S:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(Cl)C=CSc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)C=CSc2ccccc2)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
THF (45 ml) solution of 3-(phenylthio)acryloyl chloride (3.03 g) was added to THF (45 ml) solution of triethylamine (2.09 ml) under ice-cooling. 3-methylaniline (1.62 g) was added to the mixture under ice-cooling and stirred at room temperature for ten hours. The reaction solution was concentrated under reduced pressure. Ice cooled 1N hydrochloric acid (40 ml) and ethyl acetate (200 ml) were added to the residue and separated to two layer. The organic layer was washed with aqueous saturated sodium chloride solution (40 ml) twice, dried over anhydrous magnesium sulfate, filtered off inorganic salt and concentrated under reduced pressure to obtain N-(3-methylphenyl)-3-(phenylthio)acrylamide (3.46 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:9]2([OH:17])[O:14][CH2:13][C@@H:12]([CH3:15])[NH:11][C@H:10]2[CH3:16])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][CH2:28][Cl:29])=[O:26].CCCCCCC>ClCCl.O.C(OCC)(=O)C>[Cl:29][CH2:28][O:27][C:25]([N:11]1[C@H:12]([CH3:15])[CH2:13][O:14][C@:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)([OH:17])[C@@H:10]1[CH3:16])=[O:26]
Reactant: O=C(Cl)OCCl
Reactant: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCCC
Solvent: ClCCl
Product: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1C(=O)OCCl
Temperature: 5 °C
Yield: 81.1 %

Procedure:
To a stirring solution of (2S,3S,5R)-2-(3,5-difluorophenyl)-2-hydroxy-3,5-dimethylmorpholine (2.5 g, 10.28 mmol) in dichloromethane (50 mL) at room temperature under nitrogen, was added potassium carbonate (1.42 gm, 10.28 mmol). The mixture was cooled to 5° C. with a wet ice bath, and chloromethyl chloroformate (0.915 mL, 10.28 mmol) in dichloromethane (10 mL) was added dropwise. The mixture was allowed to warn to room temperature slowly and stirred over night. TLC analysis (1:1 heptane:ethyl acetate) indicated that the starting material was consumed and a new less polar spot had formed. Water was added to the mixture and then it was extracted with dichloromethane (3×). The organic layers were combined and dried over magnesium sulfate, filtered and the solvent was removed to afford a crude weight of 2.8 grams of (2S,3S,5R)-2-(3,5-difluorophenyl)-2-hydroxy-3,5-dimethylmorpholine-4-carboxylic acid chloromethyl ester (1410) as an opaque tar.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][C:17]1([CH3:35])[C:28]2=[C:29]3[N:20]([CH2:21][CH2:22][C:23](C)([CH3:33])[C:24]3=[C:25](O)[C:26](C=O)=[CH:27]2)[CH2:19][CH2:18]1.N1CCCCC1>C(#N)C>[CH3:16][C:17]1([CH3:35])[C:28]2=[C:29]3[N:20]([CH2:21][CH2:22][C:23]([CH3:24])([CH3:33])[C:15]3=[C:14]3[O:13][C:11](=[O:12])[C:10]([C:2]4[S:1][C:5]5[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:3]=4)=[CH:25][C:26]3=[CH:27]2)[CH2:19][CH2:18]1
Reactant: CC1(C)CCN2CCC(C)(C)c3c(O)c(C=O)cc1c32
Reactant: CCOC(=O)Cc1nc2ccccc2s1
Solvent: CC#N
Solvent: C1CCNCC1
Product: CC1(C)CCN2CCC(C)(C)c3c2c1cc1cc(-c2nc4ccccc4s2)c(=O)oc31
Yield: 80.4 %

Procedure:
A mixture of 12.28 g of ethyl 2-(benzothiazolyl)acetate was refluxed with 15 g of 1,1,7,7-tetramethyl-8-hydroxy-9-formyljulolidine in 120 mL of acetonitrile containing 2 mL of piperidine as a base catalyst for 15 h. Upon cooling, the precipitated bright orange solid was filtered and washed with some acetonitrile to give 19 g (79% yield) of pure dye C-545T: m.p. 229-230° C.; Tg=100° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH3:15])[C:6]=2[N:16]=1.C=O.[C:22](O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:14]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:4]=[C:3]([C:17]([NH2:19])=[O:18])[C:2]([NH:1][CH3:22])=[N:16][C:6]1=2)[CH3:15]
Reactant: CC(=O)O
Reactant: CCn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCn1c2ccccc2c2cc(C(N)=O)c(NC)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
2-amino-9-ethyl-9H-pyrido[2,3-b]indole-3-carboxamide (1, 36 mg, 0.141 mmol), formaldehyde (37 wt % in water, 0.011 mL, 0.155 mmol) and acetic acid (0.0084 mL, 0.148 mmol) in methanol (2.6 mL) were stirred at room temperature for 1 h then sodium cyanoborohydride (13 mg, 0.212 mmol) was added. The reaction stirred at room temperature for 16 h, then was quenched with aqueous saturated sodium bicarbonate (2.6 mL). The resulting mixture was diluted with ethyl acetate (100 mL), washed with water (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and then concentrated in vacuo. The residue was adsorbed onto silica gel using methanol and purified by silica gel chromatography (5-10% methanol in methylene chloride gradient) to afford the title compound (48, 25 mg, 66%). NH4OAc standard conditions. DAD Retention time =7.84 min. M+H=269. 1H NMR (300 MHz, CDCl3): δ 8.60 (br s, 1H), 8.19 (s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.36-7.32 (m, 2H), 7.21-7.17 (m, 1H), 5.65 (br s, 2H), 4.38 (q, J=7.3 Hz, 2H), 3.12 (s, 3H), 1.42 (t, J=7.3 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][OH:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[OH-].[Na+]>O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:9][CH2:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: OCCCc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCc1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
A mixture of 2-thiophenepropanol (5 g), 1,6-dibromohexane (25 g), 50% aqueous sodium hydroxide (25 ml) and TAB (500 mg) was stirred at room temperature overnight. Water (100 ml) was added and the mixture was extracted with ether (2×100 ml). The organic layer was dried and concentrated to an oil which was purified by FCC eluting with hexane to give the title compound as a colourless oil (6.6 g). T.l.c. (hexane-diethyl ether 9:1) Rf 0.50.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([F:15])=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC.[F-].[Cs+]>CN(C)C=O.C(OCC)(=O)C.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:15][C:9]1[C:8]([C:5]2[CH:4]=[C:3]([C:16]([O:18][CH3:19])=[O:17])[C:2]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[N:7][CH:6]=2)=[CH:13][C:12]([CH3:14])=[CH:11][N:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COC(=O)c1cc(-c2cc(C)cnc2F)cnc1Cl
Agent: [Cu]I
Agent: [Pd]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cc(C)cnc2F)cnc1-c1ccccn1
Temperature: 135 °C

Procedure:
To a solution of methyl 6-chloro-2′-fluoro-5′-methyl-3,3′-bipyridine-5-carboxylate (11-2, 0.098 g, 0.35 mmol, 1.0 equiv) in dimethylformamide (2.3 mL) was added 2-tri-n-butylstannylpyridine (0.26 g, 0.70 mmol, 2.0 equiv), cesium fluoride (0.16 g, 1.05 mmol, 3.0 equiv), copper (I) iodide (0.013 g, 0.070 mmol, 0.2 equiv), and tetrakis(triphenylphosphine)-palladium(0) (0.040 g, 0.035 mmol, 0.1 equiv) and the system was heated to 135° C. for 10 minutes in a microwave reactor. The reaction mixture was cooled and diluted with ethyl acetate (30 mL) and the reaction mixture was filtered through a pad of celite. The reaction mixture was washed with water (3×10 mL) and brine (1×10 mL), dried over magnesium sulfate and concentrated. The residue was purified via normal phase chromatography (10 to 100% EtOAc in hexanes, silica) to afford the desired product (11-3) as an oily solid after concentration. ESI+MS [M+H]+ C18H14FN3O2 calc'd 324.1. found 324.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]([NH:17]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:15]#[N:16]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:15]#[N:16]
Reactant: COC(=O)C(=Cc1ccc2[nH]cc(C#N)c2c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)Cc1ccc2[nH]cc(C#N)c2c1
Reaction time: 8 h
Yield: 94.9 %

Procedure:
2-Benzyloxycarbonylamino-3-(3-cyano-1H-indol-5-yl)-acrylic acid methyl ester (0.5 g, 1.3 mmol) in methanol (8 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 50 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 0.3 g (92%) of the desired material. LC/MS: tR=0.80 min, 244.20 (MH)+.