Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4](=[O:6])[CH3:5].C(Cl)(=O)C([Cl:14])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:14][CH:2]=[C:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4](=[O:6])[CH3:5]
Reactant: CC(=O)C(=CO)CC(C)C
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(=O)C(=CCl)CC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 4-hydroxy-3-isobutyl-but-3-en-2-one (28 g, 197 mmol) in chloroform (350 mL) a soution of oxalylchloride (44.3 g, 349 mmol) in chloroform (50 mL) is added slowly during 5 min. The resulting dark brown mixture is stirred at rt for 2 h before it is cooled to 0° C. and treated with ice (100 g) followed by 1 N aq. NaOH (100 mL). When the quite violent gas evolution ceases the phases are separated (the still acidic aq. phase is discarded). The organic phase is washed with 1N aq. NaOH (3×75 mL) and 1 N aq. NaH2PO4 (75 mL), dried (MgSO4), filtered and evaporated to give crude 4-chloro-3-isobutyl-but-3-en-2-one (31.6 g) as a dark brown oil; LC-MS: tR=0.97 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:29])=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>O1CCCC1>[CH3:38][N:39]1[CH2:45][CH2:44][CH2:43][N:42]([CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:29])=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:15]=3)=[O:8])=[CH:5][CH:4]=2)[CH2:41][CH2:40]1
Reactant: CN1CCCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
N-(5-(4-chloromethylbenzoylamino)-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (1 g, 2.33 mmol) was dissolved in tetrahydrofuran (20 ml), pyridine (360 ml, 4.66 mmol) was added thereto, and the mixture was stirred for 30 minutes. N-methylhomopiperazine (434 μl, 3.49 mmol) was added thereto, and the mixture was refluxed for 12 hours and filtered. The filtrate was concentrated, subjected to column chromatography (eluent: chloroform:methanol=3:1(v/v)), concentrated again, and then crystallized from dimethylether to give 4-(4-methylhomopiperazin-1-ylmethyl)-N-[4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (0.71 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[N:21][OH:22])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2F)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=3[O:22][N:21]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Nc1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc2c(Nc3ccc(Br)cc3)noc2c1
Temperature: 100 °C
Yield: 81.9 %

Procedure:
To a solution of N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)-1-benzeneamidoxime (2.25 g, 0.00598 mol) in N-methylpyrrolidinone (30 mL), potassium tert-butoxide (0.71 g, 0.00628 mol) was added and the resulting solution was heated at 100° C. under an atmosphere of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure and the residue partitioned between saturated solution of sodium bicarbonate in water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was suspended in cold n-heptane and the precipitate was collected by filtration and dried to yield N-(4-bromophenyl)-N-[6-(trifluoromethyl)benzo[d]isoxazol-3-yl]amine (1.75 g, 0.0049 mol) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:28][CH:29]=4)=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccc(C(F)(F)F)cc1
Yield: 88.5 %

Procedure:
As described for Example 9, 0.314 g of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.269 g (1.29 mmol) of 4-trifluoromethylbenzoyl chloride and 0.130 g (1.29 mmol) of triethylamine in 9 ml of dichloromethane for 1.5 hours at room temperature. The product is triturated with ethyl acetate-hexane to give 0.43 g of crystals, m.p. 205°-207° C.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3](Cl)=[O:4].[NH2:17][C:18]1[C:19]([O:29][CH3:30])=[CH:20][CH:21]=[C:22]2[C:27]=1[O:26][CH2:25][CH2:24][C:23]2=[O:28].C(N(CC)CC)C.Cl>ClCCl>[CH3:30][O:29][C:19]1[C:18]([NH:17][C:3](=[O:4])[C:2]([CH3:16])([CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:27]2[C:22]([C:23](=[O:28])[CH2:24][CH2:25][O:26]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1N)OCCC2=O
Reactant: CCCCCCCCCCC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC(C)(C)C(=O)Nc1c(OC)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
127 mg of 2,2-dimethyldodecanoyl chloride was added to a solution of 98 mg of 8-amino-7-methoxy-4-chromanone and 0.07 ml of triethylamine in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 12 hr. 15 ml of 2N hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate (25 ml×2). The extract was washed with 25 ml of brine, dried over anhydrous magnesium sulfate, filtered, concentrated and purified by silica gel column chromatography (hexane/ethyl acetate=3:2) to give 198 mg of the intended title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NCC1[CH:27]=[C:28]([CH:44]=[CH:45]C=1)[C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:33]=1)=[O:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:8][C:9]2[CH:27]=[C:28]([CH:44]=[CH:45][C:10]=2[CH3:11])[C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[CH:33]=2)=[O:30])=[O:19])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCc1cccc(C(=O)Nc2cccc(N3CCOCC3)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 18, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid was reacted with 3-aminomethyl-N-(3-morpholinophenyl)benzamide to give 3-[3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamido]4-methyl-N-(3-morpholinophenyl)benzamide in 42% yield; NMR Spectrum: (DMSOd6) 1.38 (s, 9H), 1.54 (m, 2H), 1.91 (m, 2H), 2.27 (s, 3H), 3.06 (t, 4H), 3.2 (m, 2H), 3.64 (m, 2H), 3.72 (t, 4H), 5.01 (m, 1H), 6.66 (m, 1H), 7.18 (m, 2H), 7.28 (d, 1H), 7.4 (m, 3H), 7.56 (m, 2H), 7.77 (m, 1H), 7.92 (s, 1H), 9.98 (s, 1H), 10.01 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[C:11][CH3:12])[CH2:8][CH2:7][C@H:6]1[C:13]#[N:14])=[O:4].[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(#N)C>[CH:15]1([NH:20][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]#[C:11][CH3:12])[CH2:8][CH2:7][C@H:6]2[C:13]#[N:14])=[O:4])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: NC1CCCC1
Solvent: CC#N
Product: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.018 g, 0.086 mmol) in acetonitrile (1 mL) at room temperature was added cyclopentyl amine (0.017 mL, 0.17 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/97% dichloromethane to provide the titled compound. MS (ESI) m/z 260 (M+H)+; 1H NMR (DMSO) δ ppm 4.89 (m, 1H), 4.84 (m, 1H), 4.07-4.13 (m, 2H), 3.52 (m, 1H), 2.05-2.42 (m, 4H), 1.96 (m, 2H), 1.87 (d, 3H), 1.70 (m, 4H), 1.52 (m, 2H).
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: Nc1ncnc2[nH]cnc12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(F)c1)n1cnc2c(N)ncnc21
Yield: 37 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1, using 3-(1-bromoethyl)-4-(3-fluorophenyl)-1H-isochromen-1-one (intermediate C6, 70 mg, 0.202 mmol), 9H-purin-6-amine (54.5 mg, 0.403 mmol) and K2CO3 (55.7 mg, 0.403 mmol) to give the title compound (30 mg, 37.1%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[C:17]([CH:18]=[C:19]3[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Br:25]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:25][C:18]1[C:19]2[C:24]([C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: BrBr
Reactant: c1ccc2cc(-c3c4ccccc4cc4ccccc34)ccc2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12

Procedure:
5.6 g (18.0 mmol) of 9-(2-naphthyl)anthracene and 90 mL of carbon tetrachloride were put into a 500-mL three-neck flask and stirred. A solution in which 3.2 g (20 mmol) of bromine was dissolved in 10 mL of carbon tetrachloride was dropped into the above solution through a dropping funnel. After that, the solution was stirred at the room temperature for 1 hour, and a sodium thiosulfate aqueous solution was added to the reaction solution to complete the reaction. A water layer of the reaction mixture was extracted by chloroform, and the extracted solution and an organic layer were together washed with a saturated sodium hydrogen carbonate solution and saturated saline. The organic layer was dried with magnesium sulfate, and the mixture was filtrated naturally to remove the magnesium sulfate. Then, the filtrate was condensed to obtain a solid. The obtained solid was recrystallized with ethanol, whereby 5.5 g of a yellow powdery solid, which was a target matter, was obtained with the yield of 79%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:4]=2[N:3]=1>C(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]=[O:17])=[CH:15][C:4]=2[N:3]=1
Reactant: Nc1nc2cc(CO)ccc2c2cccnc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Nc1nc2cc(C=O)ccc2c2cccnc12

Procedure:
A solution of (5-aminobenzo[f][1,7]naphthyridin-8-yl)methanol (from Example 85) (1.0 eq.) and activated MnO2 (20 eq.) in DCM (0.1 M) was stirred at ambient temperature over night. The reaction mixture was diluted with DCM. The MnO2 was filtered off, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde as a yellow solid: 1H NMR (acetone-d6): δ 10.19 (s, 1H), 9.14 (dd, 1H), 9.01 (dd, 1H), 8.63 (d, 1H), 8.14 (d, 1H), 7.93 (dd, 1H), 7.81 (dd, 1H), 6.96 (br s, 2H). LRMS [M+H]=224.1
Reaction SMILES: C(O)C.C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[N:12]=1)(C)(C)C.Cl>C(OCC)(=O)C>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([CH:17]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:13]2[N:12]=[C:11]([NH2:10])[CH:16]=[CH:15][CH:14]=2)(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)n1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.8 %

Procedure:
To an ethanol (5 ml) solution of t-butyl[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate (370 mg, 0.748 mmol) was added concentrated hydrochloric acid (5 ml). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added ethyl acetate. The resulting mixture was washed sequentially with saturated sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (210 mg, 0.537 mmol, 71%) as a white powder.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:26]([Br:27])=[CH:25][C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH2:23][CH3:24])=[O:22])[CH:16]=3)=[N:10][CH2:11][C:12](=S)[NH:13][C:7]=2[CH:6]=1)[CH2:2][CH3:3].[C:28]1([CH2:34][C:35]([NH:37][NH2:38])=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C>[CH2:1]([O:4][C:5]1[C:26]([Br:27])=[CH:25][C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH2:23][CH3:24])=[O:22])[CH:16]=3)=[N:10][CH2:11][C:12]3[N:13]([C:35]([CH2:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:37][N:38]=3)[C:7]=2[CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cc2c(cc1Br)C(c1cccc(S(=O)CC)c1)=NCC(=S)N2
Reactant: NNC(=O)Cc1ccccc1
Solvent: CCO
Product: CCCOc1cc2c(cc1Br)C(c1cccc(S(=O)CC)c1)=NCc1nnc(Cc3ccccc3)n1-2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 8-propoxy-7-bromo-1,3-dihydro-5-[m-(ethylsulfinyl)phenyl]-2H-1,4-benzodiazepine-2-thione is heated in ethanol with phenylacetic acid hydrazide and the resulting product heated to 250° C. to give 9-propoxy-8-bromo-1-benzyl-6-[ m-(ethylsulfinyl)phenyl]-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.[Cl:15]CCCl.CC(O)C>O=P(Cl)(Cl)Cl>[Cl:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(O)c2ccccc12
Reactant: ClCCCl
Solvent: CC(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(Cl)c2ccccc12
Temperature: 102.5 °C
Reaction time: 3.5 h
Yield: 76 %

Procedure:
Stir a slurry of 1-hydroxy-4-nitroisoquinoline (62.2 g, 327 mmol) in POCl3 (180 mL) mechanically under nitrogen and heat to 100-105° C. for 1 hour resulting in a homogeneous dark brown solution. Exchange the condenser for a short-path distillation head, and remove excess POCl3 under reduced pressure (ca. 10-30 torr) resulting in a pot temperature of 55° C. To this mixture add 1,2-dichloroethane (150 mL), and warn the mixture to 70° C. to obtain a homogeneous solution. Cool the solution to 15° C., then add i-PrOH (450 mL) over 5 minutes resulting in an exotherm to 33° C. Stir the slurry for 3.5 hours at 15° C. then filter and wash with i-PrOH (3×100 mL). Air-dry the resulting solid overnight to afford 1-chloro-4-nitroisoquinoline (52.08, 76% yield) as a tan solid. (ES+): m/z 209/211 (M++H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].COC(N(C1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)S([C:41]1C=CC(F)=C[C:42]=1/C=C\CO)(=O)=O)=O.N1CCCC1>>[N:3]1([CH2:4]/[CH:5]=[CH:6]\[C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[S:14]([NH:17][C:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]3[C:21]([CH:22]4[CH2:32][CH:23]4[CH2:24][O:25]3)=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH2:42][CH2:41][CH2:2][CH2:1]1
Reactant: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Solvent: C1CCNC1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCCC2)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 63, starting from methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 64) and pyrrolidine as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.CC(O[C:24]([N:26]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)C)=O)(C)C.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:31]3[CH2:32][CH2:33][CH:28]([NH:26][CH3:24])[CH2:29][CH2:30]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CNC1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
To a stirred suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (1.0 g; 3.5 mmol), 4-N-Boc-4-N-methylaminopiperidine (1.0 g; 4.7 mmol) and AcOH (0.2 mL) in 1,2-dichloroethane (25 mL) was added NaB(OAc)3H (1.0 g; 4.7 mmol). The reaction mixture was stirred at RT for 5 h upon which time it was quenched with saturated NaHCO3 solution (30 mL), diluted with H2O (50 mL) and extracted with EtOAc (200 mL). The organic layer was dried (Na2SO4) and concentrated to a yellow foam (1.84 g). This foam was dissolved in CH2Cl2 (20 mL) and treated with TFA (10 mL) at RT overnight (17 h). Volatiles were removed in vacuo, the residue was taken up in 2M HCl (30 mL) and washed with CH2Cl2 (40 mL). The aqueous layer was basified with saturated Na2CO3 solution, extracted into CH2Cl2, the organic layer separated (hydrophobic frit) and solvent evaporated to give the title compound as a pale yellow solid (1.18 g; 88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Br)=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].[H-].[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[CH:6][CH:7]=1
Reactant: BrCCc1ccc(Br)nc1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CCCN1CCc1ccc(Br)nc1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
To a mixture of dibromide 290 (1.7 g, 6.4 mmol) in 2-pyrrolidone (10 mL, 130 mmol) at room temperature was added sodium hydride, 40% dispersion in mineral oil (1.16 g, 19.3 mmol). This reaction mixture was then heated to 100° C. for 2 h, then cooled to RT and partitioned between water and ethyl acetate. The organic phase was collected, washed with water, saturated aqueous ammonium chloride, and brine. It was then dried (anhydrous MgSO4), filtered and concentrated. Silica gel chromatography (10% methanol/ethyl acetate) gave title compound 291 (1.3 g, 75% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.17-8.16 (m, 1H); 7.42-7.37 (m, 2H); 3.49 (t, J=7.4, 2H); 3.28 (t, J=6.9, 2H); 2.79 (t, J=7.2, 2H); 2.30 (t, J=7.8, 2H); 1.95 (quintet, 7.6, 2H). MS (M+H): 269.1, 271.1
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)(=O)C([Cl:13])=O>ClCCl.CN(C=O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([Cl:13])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnccn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cnccn1
Temperature: 25 °C

Procedure:
A suspension of pyrazine 2-carboxylic acid (2.52 g, 20.3 mmol) in dichloromethane (30 mL) at 0° C. was treated with oxalyl chloride (1.95 mL, 22.3 mmol) followed by the addition of catalytic DMF (1 drop). The reaction mixture was allowed to warm to room temperature overnight, then concentrated in vacuo to give pyrazine 2-carbonyl chloride as a violet-colored solid.
Reaction SMILES: [CH:1]1([C:5]2[S:9][C:8]([NH2:10])=[N:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:18]1[C:27]2[C:22](=[CH:23][C:24]([CH2:28][C:29](O)=[O:30])=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)(Cl)Cl>[CH:1]1([C:5]2[S:9][C:8]([NH:10][C:29](=[O:30])[CH2:28][C:24]3[CH:23]=[C:22]4[C:27](=[CH:26][CH:25]=3)[N:18]=[CH:19][CH:20]=[CH:21]4)=[N:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Reactant: Nc1ncc(C2CCC2)s1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc2ncccc2c1)Nc1ncc(C2CCC2)s1
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A solution of 5-cyclobutyl-thiazol-2-ylamine (Preparation 2; 30 mg, 0.195 mmol) was treated with triethylamine (81 μl, 0.585 mmol), 6-quinolylaceticacid (40 mg, 0.214 mmol) and propylphosphonic acid cyclic anhydride (T3P, 126 mL, 0.214 mmol). After 2 hours, an additional 0.2 equiv. of T3P (22 μl) was added and the reaction was complete by TLC after 15 minutes. The reaction mixture was diluted with CHCl3, was washed with saturated aqu. NaHCO3, and was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40:1 CHCl3—MeOH) to afford 55 mg of N-(5-cyclobutyl-thiazol-2-yl)-2-quinolin-6-yl-acetamide, the title compound, as a white solid.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Cl:15][C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([CH2:39][CH2:40]Cl)[CH2:35][CH2:34]3)[C:18]=2[CH:17]=1.[OH-].[Na+]>CS(C)=O.O>[ClH:15].[ClH:1].[ClH:15].[Cl:15][C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][N:36]([CH2:39][CH2:40][O:14][C:11]4[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][NH:3][CH3:2])=[CH:13][CH:12]=4)[CH2:37][CH2:38]3)[C:18]=2[CH:17]=1
Reactant: CNCCCOc1ccc(O)cc1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CNCCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Reaction time: 4 h
Yield: 33.3 %

Procedure:
A solution of 4-(3-methylaminopropoxy)phenol hydrochloride (4.7 g) and 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (10.7 g) (as its dihydrochloride) in dimethylsulfoxide (125 ml) was stirred under nitrogen during the addition of sodium hydroxide (3.46 g) in water (5 ml). The reaction was then stirred at 55° for 4 hours and then was diluted with water (500 ml). The oil which separated was extracted into ethyl acetate and hydrogen chloride was bubbled into the solution previously dried over potassium carbonate to precipitate the crude product as its trihydrochloride salt (4.3 g). Crystallization of the salt from acetonitrile-methanol yielded 1.9 g of 3-[[4-[2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-1-piperazinyl]ethoxy]phenyl]oxy]-N-methylpropanamine trihydrochloride, mp 223°-226°.