Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:44])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38](Cl)=[N:37][N:36]2[C:42]=1[Cl:43])=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:44])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:37][N:36]2[C:42]=1[Cl:43])=[O:32])[CH3:26]
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)CNC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Temperature: 95 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
0.649 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.53 g of N-(3,6-dichloroimidazo[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester were dissolved in 7 ml of 1-methyl-2-pyrrolidone; 0.345 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 24 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (185:15:2). The desired fraction was collected and recrystallized from ethyl acetate to yield 0.711 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23](/[CH:27]=[CH:28]/B(O)O)([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](/[CH:28]=[CH:27]/[C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)/C=C/B(O)O
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(/C=C/C(C)(C)C)c3O2)cc1
Yield: 81.1 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (8.0 g, 20.87 mmol) with [E]-2-tert-butylvinylboronic acid (4.01 g, 31.31 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.82 g, 1.04 mmol), and potassium carbonate (7.21 g, 52.19 mmol) generally according to the procedure described for Intermediate 37 provided 6.54 g (81%) of (±)-{7-[(1E)-3,3-dimethylbut-1-enyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a white solid. mp 85-88° C.; Anal. calcd. for C22H26O4S: C, 68.37; H, 6.78. Found: C, 68.27; H, 6.86.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C1C(=O)N([Br:22])C(=O)C1>CN(C=O)C.C(OCC)(=O)C>[Br:22][C:5]1[S:1][C:2]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NCc1cccs1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Br)s1
Temperature: 20 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
To a solution of produce tert-butyl thiophen-2-ylmethylcarbamate (1.28 g, 6 mmol, 1.0 equiv.) in DMF (4 mL) was added NBS (1.17 g, 6.6 mmol, 1.1 eq). After stirring at 20° C. for 5 h, the reaction mixture was diluted with ethyl acetate and washed with water for three times. The organic layer was dried (MgSO4) and concentrated in vacua. The residue was purified by silica gel column chromatography (PE/EtOAc=100:1 to 5:1) to afford tert-butyl (5-bromothiophen-2-yl)methylcarbamate (1.6 g, 91%). LC-MS (m/z)=235.9 [M−55]+. 1H NMR (400 MHz, DMSO-d6): δ 1.39 (s, 9H), 4.20 (d, J=6.0 Hz, 2H), 6.76 (d, J=4.0 Hz, 1H), 7.03 (d, J=3.6 Hz, 1H), 7.52 (t, J=5.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1
Reactant: CCCCCI
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Product: CCCCCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
5-(4,4-Dimethyl-oxo-1,4-dihydro-2H-3,1-benzoxazine-6-yl)-1H-pyrrole-carbonitrile (1.94 g, 7.3 mmol) was reacted, according to General Method A, with 1-iodopentane (1.5 g, 7.6 mmol) to afford the title compound, m.p. 128-131° C. (0.2 g, 8%); 1H-NMR (DMSO-d6) δ0.73 (t, J=7.3 Hz, 3H), 1.05 (m, 2H), 1.14 (m, 2H), 1.57 (m, 2H), 1.63 (s, 6H ), 4.04 (t, J=7.5 Hz, 2H), 6.28 (d, J=4 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 7.04 (d, J=4.5 Hz, 1H), 7.33 (dd, J=8.9, 2.0 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 10.41 (s, 1H), MS (APCI (−)) m/z 336 (M−H)−
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7].[CH:42](=[O:44])[CH3:43]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][C:19]([CH:42]([OH:44])[CH3:43])=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7]
Reactant: CC=O
Reactant: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3cc(C(C)O)sc3c12)c1ccccc1

Procedure:
By lithiation of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide and reaction with acetaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-].[Na+].S(OC)(O[CH3:23])(=O)=O.N>O>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:23])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: COS(=O)(=O)OC
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)c2ccccc2)c(O)c1
Reaction time: 0.5 h
Yield: 463.4 %

Procedure:
214 g ( =1.0 mole) of 2,4-dihydroxybenzophenone were added to a mixture of 500 ml of 2 N sodium hydroxide solution and 150 ml of water at room temperature and stirring was carried out until everything had dissolved (20 minutes). Thereafter, 31.6 ml (=0.33 mole) of dimethyl sulfate were added and stirring was continued for 0.5 hour, after which a further 31.6 ml (=0.33 mole) of dimethyl sulfate were added while stirring. After 0.5 hour, a further 31.6 ml (=0.33 mole) of dimethyl sulfate were added while stirring and, after 0.5 hour, 50 ml of 2 N sodium hydroxide solution and 9.5 ml of dimethyl sulfate were added. The mixture was stirred for 1 hour at room temperature, 30 ml of concentrated ammonia solution were added and stirring was then continued for a further 0.5 hour. The precipitate which had separated out was filtered off under suction and washed with a little water to give 349 g (202.4 g of dry product=89% of theory) of moist 2-hydroxy-4-methoxybenzophenone, which contains 1.07% of 2,4-dimethoxybenzophenone. The moist filtration residue was recrystallized from 1,170 ml of methanol with the addition of 5 g of active carbon. After filtration under suction and drying under reduced pressure from a water pump at 50° C., 171 g (=75% of theory) of pure 2-hydroxy-4-methoxybenzophenone of melting point 62°-63° C. were obtained. According to gas chromatography, the product did not contain any dimethoxy derivative.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C@H:14]([C@@:20]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)([NH:22][CH:23]([CH3:25])[CH3:24])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=O)[CH:11]=[CH:12][CH:13]=1.CN(C=O)C>C1C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:14]2[C@:20]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:21])[N:22]([CH:23]([CH3:24])[CH3:25])[C:17](=[O:19])[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)N[C@](C)(c1ccc(Cl)cc1)[C@H](CCC(=O)O)c1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@@]1(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Oxalyl chloride (˜0.38 M in benzene, 0.617 mL, 0.234 mmol) was added to a room temperature solution of (4R,5S)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-(isopropylamino)hexanoic acid (Example 418, Step G, 84 mg, 0.213 mmol) in benzene (3 mL) followed by a drop of DMF. The reaction solution was stirred at room temperature for 25 minutes then heated to 80° C. After 3.5 hours the reaction was removed from heat and saturated aqueous sodium bicarbonate solution was added. The organic phase was diluted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, then dried with anhydrous magnesium sulfate and concentrated to afford a red-orange oil. The product was isolated by chromatography on silica (12 g RediSep Rf cartridge) eluting with 20-40% ethyl acetate gradient in hexane to afford the title compound as a pale yellow film. [α]D=+ 89.33° (T=24.0° C.; c=1, CHCl3)
Reaction SMILES: C([N:8]1[C:20]2[C:19]([OH:21])=[C:18]3[N:22](C(OC(C)(C)C)=O)[C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([F:37])[CH:13]=2)(OC(C)(C)C)=O.Cl.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]Cl.C([O-])([O-])=O.[K+].[K+].FC(F)(F)C(O)=O>CC(C)=O>[F:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:18]1[C:19]([O:21][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[C:20]3[NH:8][C:9]4[CH:10]=[CH:11][C:12]([F:37])=[CH:13][C:14]=4[C:15]3=[CH:16][C:17]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(F)cc2c2cc3c4cc(F)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2cc2c1[nH]c1ccc(F)cc12
Temperature: 25 °C
Yield: 64.5 %

Procedure:
A mixture of 5,7-diBOC-2,10-difluoro-6-hydroxyindolo[2,3-b]carbazole (406.8 mg, 0.8 mmol), 2-(dimethylamino)ethyl chloride hydrochloride (126.8 mg, 0.88 mmol) and K2CO3 (10 equivalents) in 4A-molecular-sieve-dried acetone (40 mL) was magnetically stirred and heated to reflux under Ar. After the reaction was complete, it was cooled to room temperature. The inorganic salt was removed by filtration and washed with a small quantity of acetone. The combined acetone solution was concentrated on a rotavapor and dried under vacuum pump. The crude product was purified by flash chromatography. The resultant product 2-(2,10-difluoro-5,7-diBOC-indolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine was dissolved in CH2Cl2 (40 mL), and trifluoroacetic acid (˜40 equivalents) was added. The reaction was stirred at room temperature overnight, concentrated, and dried under vacuum pump. The crude compound was dissolved in ethyl acetate (40 mL), washed with saturated NaHCO3 solution, dried under Na2SO4, concentrated, and flash chromatography to provide the desired product 2-(2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine (195.9 mg, 65%). 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.40 (s, 2 H), 8.56 (s, 1 H), 7.87 (dd, J=9.2, 2.4 Hz, 2 H), 7.44 (dd, J=8.4, 4.4 Hz, 2 H), 7.20-7.11 (m, 2 H), 4.30 (t, J=5.8 Hz, 2 H), 2.72 (t, J=5.8 Hz, 2 H), 2.32 (s, 6 H); MS (ESI) m/z 378.1 (M−H)−; MS (ESI) m/z 380.1 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:38][OH:39])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([CH:32]([OH:35])[CH2:33][OH:34])=[CH:30][CH:31]=[C:26]4[C:25]([C:36]#[N:37])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:42])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:38][OH:39])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([CH:32]([OH:35])[CH2:33][OH:34])=[CH:30][CH:31]=[C:26]4[C:25]([C:36]([NH2:37])=[O:42])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(C(O)CO)nc54)c3CO)ncc2c1
Reactant: CCO
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccc(C(O)CO)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(1,2-dihydroxyethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (14 mg, 26.5 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (373 μg, 0.870 μmol, Eq: 0.0328) were combined with Ethanol (200 μl) and Water (200 μl) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo. Mixture was diluted with acetonitrile and water and filtered. The resultant filtrate is lyophilized to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(1,2-dihydroxy-ethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (11.2 mg, 77%, [M+H]+ 546).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH2:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH:49]([C:57]([NH2:59])=[O:58])[NH:48]1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:48]2[CH:49]([C:57]([NH2:59])=[O:58])[CH2:50][C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:47]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: NC(=O)C1Cc2ccccc2CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2oncc2C(=O)N2Cc3ccccc3CC2C(N)=O)cc1
Reaction time: 2 h
Yield: 22.1 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (20 mg, 0.1 mmol), TBTU (39 mg, 0.12 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (35 μL, 0.2 mmol, 2 equ) in DMF (1 mL) was added to 1,2,3,4-tetrahydroisoquinoline-3-carboxamide (18 mg, 0.1 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C21H19N3O3: 361.1426, found 361.1418.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([CH:7]=1)[O:8][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Oc1cc(Br)cc(F)c1F
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(Br)cc(F)c1F
Temperature: 80 °C
Yield: 91 %

Procedure:
To a solution of 5-bromo-2,3-difluorophenol (Avocado, 2.5 g, 12.0 mmol) in DMF (50 mL) was added ethyl 4-bromobutyrate (2.57 g, 13.2 mmol) and K2CO3 (2.5 g, 18 mmol). The reaction mixture was heated at 80° C. for 3 hours. The reaction mixture was diluted with EtOAc and washed with water (3×) and brine, dried (MgSO4) and concentrated under vacuum affording the title compound as a colorless oil (3.53 g, 91%). 1H NMR (DMSO-d6, 300 MHz) δ 7.36 (m, 1H), 7.28 (m, 1H), 4.16-4.03 (m, 4H), 2.45 (t, 2H), 2.03-1.94 (m, 2H), 1.18 (t, 3H). LC/MS (Method B): 323.1, 325.0 (M+H)+. HPLC (Method A) Rt 4.94 min (Purity: 99.8%).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:18])[C:7]=1[C:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:17][O:16][CH2:15]2)[CH2:12][CH:13]=1.[C:19](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:20].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>[F:18][C:6]1[C:7]([C:8]2[CH2:9][CH2:10][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:12][CH:13]=2)=[C:2]([NH:20][C:19](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: Fc1cncc(Cl)c1C1=CCN(C2COC2)CC1
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Product: CC(C)(C)OC(=O)Nc1cncc(F)c1C1=CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.2 %

Procedure:
3-chloro-5-fluoro-4-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]pyridine (572 mg, 2.129 mmol), tert-butyl carbamate (1.246 g, 10.64 mmol), sodium tert-butoxide (1.044 g, 10.86 mmol), BrettPhos pre-catalyst (84.78 mg, 0.1064 mmol) and BrettPhos (57.11 mg, 0.1064 mmol) were placed in a sealable tube and degassed by vacuum/nitrogen cycles (×5). Dry dioxane (10 mL) was added and the resulting mixture was placed into a pre-heated block at 100° C. and stirred at this temperature for 16 hours. The reaction mixture was cooled to ambient temperature and quenched with saturated NH4Cl. The mixture was passed through a pre-wetted (EtOAc) celite cartridge (2.5 g). The cartridge was washed with EtOAc/saturated NH4Cl and the layers of the filtrate separated. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column, eluting with 0 to 100% EtOAc/Petroleum Ether, loaded in DCM) to give tert-butyl (5-fluoro-1′-(oxetan-3-yl)-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridin]-3-yl)carbamate as a pale yellow solid (180 mg, 24% Yield). Also isolate 197 mg of a mixture of SM and product. MS (ES+) 350.2.
Reaction SMILES: C[NH:2]CCO.F[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:2][C:13]1[CH:14]=[CH:7][CH:8]=[CH:9][C:10]=1[CH:11]=[O:12]
Reactant: CNCCO
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ccccc1C=O
Temperature: 95 °C

Procedure:
A reactor is charged with 2-(methylamino)ethanol (134 g, 1.8 moles), 4-fluorobenzaldehyde (74.4 g, 0.6 mole), potassium carbonate (82.8 g, 0.6 mole) and dimethylsulfoxide (750 ml), and the mixture is heated at 95° C. for 72 hours. The product mixture is cooled and poured into three liters of ice water. The yellow solid that precipitates is filtered, washed with water, and dried in a vacuum oven, mp 72° C. The 4-[N-(2-hydroxyethyl)-N-methylamino]benzaldehyde product is recrystallized from water as needle-like crystals.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][N:14]3[C:23]4[N:19]([C:20]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)=[N:21][N:22]=4)[CH2:18][CH2:17][CH2:16][CH2:15]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N>[N:27]1[CH:28]=[CH:29][C:24]([C:20]2[N:19]3[C:23]([N:14]([CH2:13][C:10]4[N:11]=[N:12][N:8]([C:4]5[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=5)[C:30]#[N:31])[N:9]=4)[CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:22][N:21]=2)=[CH:25][CH:26]=1
Reactant: Ic1cccc(-n2nnc(CN3CCCCn4c(-c5ccncc5)nnc43)n2)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(-n2nnc(CN3CCCCn4c(-c5ccncc5)nnc43)n2)c1

Procedure:
The title compound is prepared from 8-[2-(3-iodo-phenyl)-2H-tetrazol-5-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:3].C(O)(=O)C.[CH:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1)=O>C(O)C>[CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:3]=[CH:14][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: CN(N)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CN(N=Cc1ccnc2ccccc12)c1ccccc1
Temperature: 0 °C

Procedure:
One equivalent of methylphenylhydrazine (4.1 g; 0.033 mol, compound 2 was diluted in 25 ml of ethanol and 0.5 ml of glacial acetic acid in a three-necked flask on which was mounted a condenser. The reaction medium was then stirred at 0° C. 1 equivalent of 4-formylquinoline (5.28 g; 0.033 mol, compound 14) was added by spatula. After adding the aldehyde, the reaction medium was heated at 70° C. (oil bath temperature) for 4 hours.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][C:5]([CH3:11])=[C:6]([C:8](=[O:10])[CH3:9])[N:7]=1.[BrH:14].BrBr>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[S:4][C:5]([CH3:11])=[C:6]([C:8](=[O:10])[CH2:9][Br:14])[N:7]=1
Reactant: Br
Reactant: CC(=O)c1nc(C(F)(F)F)sc1C
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1sc(C(F)(F)F)nc1C(=O)CBr
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
3 g (0.0144 mol) of 2-Trifluoromethyl-5-methyl-4-acetyl-thiazole are dissolved in 30 ml of glacial acetic acid, and 2.1 ml of a 33% strength solution of hydrogen bromide in glacial acetic acid are added. The mixture is heated to 80° C. and, over the course of 30 minutes, a solution of 2.3 g (0.0144 mol) of bromine in 15 ml of glacial acetic acid is added. After a further 20 minutes, the glacial acetic acid is removed. The residue which remains is a dark oil which is reacted further as the crude product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[C:13]([NH2:17])(=[O:16])[CH:14]=[CH2:15].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:15][CH2:14][C:13]([NH2:17])=[O:16])=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:3]=1
Reactant: C=CC(N)=O
Reactant: FC(F)(F)c1cc(Br)ccc1S
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Solvent: O
Solvent: CO
Product: NC(=O)CCSc1ccc(Br)cc1C(F)(F)F
Reaction time: 40 h
Yield: 98.2 %

Procedure:
4-Bromo-2-trifluoromethyl-benzenethiol (259.2 g, 1.01 mol) was dissolved in methanol (1.3 L) and water (2.6 L), then acrylamide (130 g, 1.82 mol), followed by sodium tetraborate (25.9 g, 129 mmol) were added at room temperature. The suspension was stirred for 40 h. After filtration, the solid was washed with water (2.6 L) and n-heptane (2.6 L) and dried in vacuo to yield the title compound as a white powder (325.6 g, 98%). MS (EI): m/z=330.0, 328.0 [M+H]+. 1H NMR (d6-DMSO, 400 MHz): δ 2.40 (t, J=7.2 Hz, 2H), 3.24 (t, J=7.2 Hz, 2H), 6.92 (bs, 1H), 7.37 (bs, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.82-7.88 (m, 2H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[CH2:10][CH2:11]O)=O)(C)(C)C.O=S(Cl)Cl.[CH3:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[N:30]=[C:31]=[S:32]>>[CH:13]([C@H:9]1[CH2:10][CH2:11][S:32][C:31](=[N:30][C:22]2[CH:23]=[CH:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][C:21]=2[CH3:20])[NH:8]1)([CH3:15])[CH3:14]
Reactant: CC(C)[C@@H](CCO)NC(=O)OC(C)(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](C(C)C)CCS1
Yield: 100 %

Procedure:
(R)-3-(tert-Butoxycarbonylamino)-4-methylpentanol (Method B6a) was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to afford (R)-4-isopropyl-2-(2-methyl-4-nitrophenylimino)-2,3,4,5-tetrahydro-1,3-thiazine (100%).