Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4]O.S(Cl)([Cl:14])=O.CN(C=O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][Cl:14]
Reactant: O=S(Cl)Cl
Reactant: OCc1c(Cl)cc(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: ClCc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a stirred solution of 2,4,6-trichlorobenzylalcohol (10.0 g; 47.3 mmoles) in chloroform (100 ml) kept under nitrogen atmosphere, thionyl chloride (6.07 mL, 85.1 mmole) was added slowly at 0° C. over a period of 15 minutes followed by catalytic amount of DMF. The reaction mix was allowed to stir at ambient temp for 3 hours. The reaction mixture was quenched with 50 mL of water; the aqueous layer was extracted with DCM (3×100 ml). The combined organic layer was washed with 5% sodium bicarbonate solution (2×50 ml) followed by brine (50 ml) and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure. 10.9 g (100.0% of theory) of 1,3,5-trichloro-2-chloromethyl-benzene was obtained in form of a white solid.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[N:14]=[C:13]([Sn](CCCC)(CCCC)CCCC)[CH:12]=[CH:11][CH:10]=1.Br[C:29]1[N:33]2[N:34]=[C:35]([N:38]3[CH2:42][CH2:41][CH2:40][CH:39]3[C:43]3[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=3[F:50])[CH:36]=[CH:37][C:32]2=[N:31][CH:30]=1>C1(C)C=CC=CC=1>[F:50][C:44]1[CH:45]=[CH:46][C:47]([F:49])=[CH:48][C:43]=1[CH:39]1[CH2:40][CH2:41][CH2:42][N:38]1[C:35]1[CH:36]=[CH:37][C:32]2[N:33]([C:29]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([F:8])[N:14]=3)=[CH:30][N:31]=2)[N:34]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(F)n1
Reactant: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(-c4cccc(F)n4)n3n2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
In step 5-1, triethylamine (0.045 mL, 0.29 mmol), tetrakis(triphenylphospine)palladium (0) (12 mg, 0.01 mmol), and 6-fluoro-2(tributylstannyl)pyridine (80 mg, 0.201 mmol) were added to a solution of 3-bromo-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (6-6) (53 mg, 0.13 mmol) in 3 mL of toluene. The reaction mixture was heated to 100° C. and stirred for 6 hours at 100° C. The reaction mixture was then cooled to room temperature and purified using flash chromatography (ethyl acetate and hexanes (1:1)) giving 6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine (5-1). 1H NMR (400 MHz, D3 acetonitrile) δ ppm 8.35-8.17 (m, 2H), 8.02-7.83 (m, 1H), 7.48-7.22 (m, 3H), 7.15-6.92 (m, 3H), 5.42 (br d, J=5.8 Hz, 1H), 4.12-3.99 (m, 1H), 3.81-3.72 (m, 1H), 2.70-2.56 (m, 1H), 2.30-2.06 (m, 3H). LCMS observed m/z 396.1
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13]([N:21]=[C:22]([S-])[S-:23](C)[CH3:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH3:24][S:23][C:22]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[N:21][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: C[S-](C)C([S-])=NC(=O)c1ccccc1
Solvent: ClCCl
Product: CSC(=NC(=O)c1ccccc1)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a mixture of 1-(2-pyridyl)piperazine (10 ml, 64.37 mmol) in dichloromethane (200 ml) was added N-benzoyldimethyldithioimidocarbonate (14.64 g, 65.01 mmol) and the reaction mixture was stirred for 18 h at room temperature. The volatiles were evaporated in vacuo and the residue crystallised from a mixture of heptane/diethyl ether 9:1. The solid was filtered off, washed with a mixture of heptane/diethyl ether 1:1 and dried in vacuo affording 20.86 g of N-[methylsulfanyl-(4-(pyridin-2-yl)piperazin-1-yl)methylene]-benzamide as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([Cl:12])[CH:6]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Br:14])=[C:7]([Cl:12])[CH:6]=1
Reactant: COC(=O)Nc1ccc(C)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Nc1ccc(CBr)c(Cl)c1
Reaction time: 20 h
Yield: 55.5 %

Procedure:
To a stirred solution of 10.9 grams (0.055 mole) of methyl(3-chloro-4-methylphenyl)carbamate in 110 ml of carbon tetrachloride, under an argon atmosphere, was added 9.7 grams (0.055 mole) of N-bromosuccinimide. The reaction mixture was irradiated with a 250 watt brooder lamp, placed at such a distance as to cause a gentle reflux. The reflux was continued for 20 hours. The reaction mixture was cooled and a solid collected by filtration. The solid was slurried with water and the insoluble material collected by filtration. The filter cake was dried to give 8.5 grams of methyl(4-bromomethyl-3-chlorophenyl)carbamate; m.p. 128°-131° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:22][CH3:23])=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Br:19])=[CH:14][C:13]([O:20][CH3:21])=[CH:12][CH:11]=3)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:29]>ClCCl.CO>[C:1]([O:4][C:5]1[C:6]([O:22][CH3:23])=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16](=[O:29])[C:17]=2[C:18]=1[Br:19])=[CH:14][C:13]([O:20][CH3:21])=[CH:12][CH:11]=3)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)Sc1c(cc(OC)c(OC(C)=O)c1Br)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)S(=O)c1c(cc(OC)c(OC(C)=O)c1Br)N2
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 3-acetoxy-4-bromo-2,7-dimethoxy-10H-phenothiazine (10.0 g) in dichloromethane (125 ml) and methanol (125 ml) there was added at room temperature 85% m-chloro peroxybenzoic acid (4.36 g). The mixture was stirred for one hour and the solid was filtered and washed with ether. This crude product was stirred at room temperature in dichloromethane (50 ml) overnight and filtered again to afford pure title product (7.7 g). m.p.: 243°-247° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 4-hydroxybenzaldehyde (19.2 g, 157.5 mmol), 2,6-dichlorobenzylbromide (36 g, 150 mmol) and potassium carbonate (22.77 g, 165 mmol) in DMF (150 ml) was stirred at room temperature overnight. The mixture was filtered and the filtrate evaporated under reduced pressure. The residue was dissolved in ether (500 ml), and washed with aqueous NaOH (5%, 100 ml), water (100 ml) and brine (100 ml), dried (Na2SO4) and evaporated under reduced pressure. The orange crystalline solid obtained was recrystallised from diisopropylether to give the title compound as slightly orange needles (35.8 g, 85%), m.p. 70-71°. δH (CDCl3) 9.91 (1H, s, CHO), 7.87 (2H, d, J 8.9 Hz, ArH), 7.40-7.24 (3H, m, ArCl2H), 7.12 (2H, d, J 8.7 Hz, ArH) and 5.36 (2H, s, ArCH2OAr); m/z (ESI, 60V) 281 (M++1); Found: C, 59.76; H, 3.57. C14H10O2Cl2 requires C, 59.81; H, 3.59%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[O:55]1[CH:59]=[CH:58][C:57]([C:60](O)=[O:61])=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:57]2[CH:58]=[CH:59][O:55][N:56]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)c1ccon1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccon2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 37 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and isoxazole-3-carboxylic acid as starting materials in 37% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.41 (m, 2H), 9.02 (m, 2H), 8.30 (m, 2H), 8.20 (s, 1H), 7.64 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 6.80 (s, 1H), 4.52 (m, 1H), 3.83 (m, 1H), 3.18 (m, 2H), 2.98 (m, 4H), 2.32 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C28H28ClN8O3 (M+H)+: m/z=559.2.