Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]=[CH:7][C:6]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:14])=[C:5]2[OH:24].[CH2:25]([OH:28])[C:26]#[CH:27].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:13]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[OH:24])=[CH:3][C:2]([C:27]#[C:26][CH2:25][OH:28])=[C:11]([CH3:12])[N:10]=3)=[O:14])=[CH:18][CH:19]=1
Reactant: Cc1nc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1Br
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1C#CCO
Yield: 35.4 %

Procedure:
A solution of 6-bromo-N-(4-chlorobenzyl)-4-hydroxy-7-methyl[1,8]naphthyridine-3-carboxamide (0.244 g, 0.60 mmol), propargyl alcohol (0.047 g, 0.84 mmol), triethylamine (0.38 mL) and PdCl2(PPh3)2 (0.023 g, 0.03 mmol) in 3 mL DMF is heated to 90° C. for 2.5 h. The resulting solution is cooled and partitioned between EtOAc and water. The solid which formed is filtered and discarded. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed on silica (Biotage flash 40S, eluent 2% MeOH/CH2Cl2 then 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and condensed to yield 0.081 g (35%) of the desired product as a yellow solid. Physical characteristics are as follows: m.p. 279-281° C. (dec.); 1H NMR (DMSO-d6) δ13.19, 10.12, 8.64, 8.43, 7.38, 5.46, 4.54, 4.40, 2.71; IR (drift) 3194, 3065, 2944, 1645, 1597, 1566, 1522, 1488, 1418, 1357, 1257, 1208, 1015, 851, 809 cm−1; OAMS supporting ions at: ESI+ 381.9 ESI− 379.9; HRMS (FAB) calcd for C20H16CIN3O3 +H1 382.0958, found 382.0960.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)=[C:20]([O:32][CH3:33])[CH:19]=2)=[C:4]2[N:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:17].C(N(CC)CC)C.[C:41](Cl)(=[O:44])[CH:42]=[CH2:43]>C(Cl)Cl>[NH2:17][C:5]1[C:4]2=[C:3]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)=[C:20]([O:32][CH3:33])[CH:19]=3)[C:2]([Cl:1])=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:41](=[O:44])[CH:42]=[CH2:43])[CH2:12]3)[N:9]2[N:8]=[CH:7][N:6]=1
Reactant: COc1cc(-c2c(Cl)c(C3CCCNC3)n3ncnc(N)c23)ccc1Oc1cccc(Cl)c1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCCC(c2c(Cl)c(-c3ccc(Oc4cccc(Cl)c4)c(OC)c3)c3c(N)ncnn23)C1
Temperature: -10 °C

Procedure:
The compound (27.6 mg, 0.057 mmol) prepared in Example 31 was taken up in 1 mL DCM (dry) under argon and triethylamine (23.8 μl, 0.171 mmole) was added. The reaction was cooled to −10° C. and the acryloyl chloride (4.17 μl, 0.051 mmole) was added via syringe slowly. The reaction quenched with methanol and solvent removed under vacuum. The title compound (10.5 mg) having the following data was isolated by prep-HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:10]=[CH:11]/[C:12]([OH:14])=O)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:37][CH2:38][C:39]1[N:43]([C:44]2[S:45][C:46]([CH2:58][CH3:59])=[CH:47][C:48]=2[C:49](=[O:57])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:56])[C:42]([CH3:60])=[N:41][N:40]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[Cl:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[C:49]([C:48]1[CH:47]=[C:46]([CH2:58][CH3:59])[S:45][C:44]=1[N:43]1[C:42]([CH3:60])=[N:41][N:40]=[C:39]1[CH2:38][NH:37][C:12](=[O:14])/[CH:11]=[CH:10]/[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:57]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C(O)/C=C/c1ccccc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)/C=C/c2ccccc2[N+](=O)[O-])s1
Yield: 68.2 %

Procedure:
Reaction was carried out in the same manner as in Example 186 using trans-3-(2-nitrophenyl)propenoic acid (1.93 g), 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (7.42 g), triethylamine (5.6 ml) and 1-benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent, 4.42 g), and the obtained crude crystals were recrystallized from ethyl acetate to give 3.65 g of trans-N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-(2-nitrophenyl)propenamide.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[CH2:33]/[C:34](=[N:37]/[H])/[NH:35]O.[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:35]=[C:34]([CH2:33][C:27]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=3[Cl:25])[N:37]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: [H]/N=C(/Cc1ccc(F)cc1Cl)NO
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCc2nc(Cc3ccc(F)cc3Cl)no2)c(=O)c2[nH]c(Cl)nc21
Yield: 52.6 %

Procedure:
Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (100 mg, 0.28 mmol) and (1Z)-2-(2-chloro-4-fluorophenyl)-N-hydroxyethanimidamide (62.4 mg, 0.308 mmol) and 21% by wt. ethanolic sodium ethoxide (0.157 ml, 0.42 mmol) were heated together in a microwave reactor in EtOH (1.5 ml) at 140° C. for 10 min. The mixture was worked up by partitioning between EtOAc and 2M HCl. The organic phase was evaporated and purified by MDAP to afford the title compound as a solid (73 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]1[CH2:24][CH3:25].S(Cl)([Cl:29])(=O)=O.O>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]1([CH2:24][CH3:25])[Cl:29]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCC1C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCC1(Cl)C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1c1ccccc1
Temperature: 25 °C

Procedure:
(1-Oxo-2-ethyl-3-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (5.6 g., 0.0143 mole) is dissolved in warm acetic acid (70 ml.) and treated with sulfuryl chloride (1.3 ml., 0.016 mole). The solution is heated on a steam bath for two hours, cooled to room temperature and then added slowly to cold water (500 ml.) with stirring. The product precipitates and is collected by suction filtration, washed well with water and air-dried overnight to afford 5.9 g. of crude product. The crude product is recrystallized several times from ethanol (30 ml.) and water (20 ml.) and then from nitromethane to afford substantially pure (1-oxo-2-ethyl-3-phenyl-2,6,7-trichloro-5-indanyloxy)acetic acid, m.p. 190°-192° C.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.CN1CCOCC1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25](Cl)=[O:26]>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25]([N:2]([C@@H:3]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:1])=[O:26]
Reactant: CN[C@H](CN1CCCC1)C(C)(C)C
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C(=O)c1ccc(Cl)c(Cl)c1)[C@H](CN1CCCC1)C(C)(C)C
Yield: 74.4 %

Procedure:
To a solution of (S)—N,3,3-trimethyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M1) (75 mg, 0.41 mmol) in DMF (1.5 mL) was NMM (0.049 mL, 0.45 mmol) and 3,4-dichlorobenzoyl chloride (0.074 mL, 0.53 mmol) added. The resultant mixture was stirred at rt overnight. The mixture was concentrated and the residue dissolved in DCM (5 mL). The organic phase was washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (109 mg, 75%). Mixture of rotamers: 1H NMR (400 MHz, DMSO-d6) δ 0.97, 1.35-1.99, 2.07-2.43, 2.52-2.73, 2.93-3.18, 4.57, 6.86-7.18, 7.18-7.37, 7.37-7.61, 7.61-7.88. Total no of protons: 26. HRMS (M+H)+: calculated 357.1500. found 357.1470.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[N:27]1[C:32]2=[N:33][C:34]3[C:35](=[C:36]([CH:40]=[O:41])[CH:37]=[CH:38][CH:39]=3)[N:31]2[CH2:30][CH2:29][CH2:28]1.C[Si](C)(C)[C:44]([F:47])([F:46])[F:45]>O1CCCC1.Cl>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[N:27]1[C:32]2=[N:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]([OH:41])[C:44]([F:47])([F:46])[F:45])[C:35]=3[N:31]2[CH2:30][CH2:29][CH2:28]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 66.1 %

Procedure:
Tetra-n-butylammonium fluoride (1.0 M solution in tetrahydrofuran, 1.3 mL, 1.3 mmol) was added dropwise to a stirred solution of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (1.50 g, 4.33 mmol) and trimethyl(trifluoromethyl)silane (1.83 g, 12.9 mmol) in tetrahydrofuran (11 mL) at 0° C., and the mixture was stirred at room temperature for 10 hr. The mixture was diluted with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (1.19 g, 2.86 mmol, 66%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:13][NH2:14])[CH:6]=[CH:7][C:8]=1[S:9](=[O:12])(=[O:11])[NH2:10].[F:15][C:16]([F:35])([F:34])[C:17](=O)[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][S:30][CH:31]=2)=[C:23]([CH3:32])[CH:22]=1)=O>>[Cl:2][C:3]1[CH:4]=[C:5]([N:13]2[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[N:28]=[CH:29][S:30][CH:31]=4)=[C:23]([CH3:32])[CH:22]=3)=[CH:18][C:17]([C:16]([F:35])([F:34])[F:15])=[N:14]2)[CH:6]=[CH:7][C:8]=1[S:9]([NH2:10])(=[O:11])=[O:12]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1cscn1
Reactant: NNc1ccc(S(N)(=O)=O)c(Cl)c1
Agent: Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)c(Cl)c2)ccc1-c1cscn1

Procedure:
The title compound was prepared according to the procedure of Example 60 using 3-chloro-4-sulfamoylphenylhydrazine hydrochloride instead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride and 4,4,4-trifluoro-1-[3-methyl-4-(4-thiazolyl)phenyl]butane-1,3-dione instead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione in step 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2.C1(C)C=CC=CC=1>C(O)(=O)C>[F:14][C:13]([F:15])([F:16])[C:10]([CH:11]=[N:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2)([OH:17])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21])([CH3:18])[CH3:19]
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2[nH]ncc12
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1C(C)(C)CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h
Yield: 89.5 %

Procedure:
300 mg (0.813 mmol) of 4-(5-bromo-2-methoxyphenyl)-2hydroxy-4-methyl-2-(trifluoromethyl)pentanal is mixed in 1.19 ml of glacial acetic acid with 108.2 mg (0.813 mmol) of 4-aminoindazole, and it is stirred for four days at room temperature. The batch is spun in until a dry state is reached, and the residue is drawn off three times with toluene. Chromatography on silica gel (mobile solvent:ethyl acetate/hexane) yields 352.5 mg (89.5%) of the desired imine (together with the imine of the Desbrom compound).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH2:16][CH:15]1[C:18](=[NH:25])[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.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH:1]([N:14]1[CH2:17][CH2:16][CH:15]1[CH:18]([NH2:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NC(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Add 5.0 g of 1-benzhydryl-2-benzimidoylazetidine to an ice cold suspension of 1.16 g of lithium aluminum hydride in 135 ml of dry ether. Stir the mixture at 0° C for 15 minutes, then allow the mixture to warm to room temperature and continue stirring for 18 hours. Cool the suspension to 0° C and cautiously quench by the successive addition of 1.25 ml of water, 1.75 ml of 10% aqueous sodium hydroxide, and 3.5 ml of water. Stir, filter and wash the precipitate with ether. Combine the ether washes with the original filtrate and wash the resultant solution successively with water and brine. Dry over anhydrous sodium sulfate, and remove ether in vacuo.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]([C@@H:10]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9]>N1C=CC=CC=1.ClCCl>[CH3:6][O:7][C:8]([C@@H:10]1[CH2:14][C@@H:13]([O:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Add methanesulfonyl chloride (1.56 mol, 179 g) drop wise to a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.65 mol, 160 g) in pyridine (600 mL) at 0° C. under a nitrogen atmosphere. Upon complete addition, warm the reaction mixture to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane, wash with 0.1 N hydrochloric acid solution and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the title compound (185 g, 91%) as a thick oil. ES-MS m/z 324.1 [M+1]+, 224.0 [M−Boc]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]=[C:12]([NH:15][C:16]3[N:21]=[CH:20][C:19]([S:22][CH2:23][CH2:24][C:25](OC)=O)=[CH:18][C:17]=3[O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:13][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].ClC1C=C[N:40]=[C:39]([C:43]([NH:45][CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])=[O:44])[CH:38]=1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[N:11]=[C:12]([NH:15][C:16]3[N:21]=[CH:20][C:19]([S:22][C:23]4[CH:24]=[CH:25][N:40]=[C:39]([C:43]([NH:45][CH2:46][CH2:47][N:48]([CH3:49])[CH3:50])=[O:44])[CH:38]=4)=[CH:18][C:17]=3[O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:13][CH:14]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(C)=O)CC3)cs2)c(Oc2ccccc2)c1
Reactant: CN(C)CCNC(=O)c1cc(Cl)ccn1
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Sc4ccnc(C(=O)NCCN(C)C)c4)cc3Oc3ccccc3)n2)CC1

Procedure:
Prepared from methyl 3-(6-(4-(1-acetylpiperidin-4-yl)thiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate and 4-chloro-N-(2-(dimethylamino)ethyl)picolinamide as described in Example 3, Step C. 1H NMR (CDCl3) δ 1.62-1.70 (m, 2H), 2.07-2.12 (m, 2H), 2.11 (s, 3H), 2.28 (s, 6H), 2.51 (t, 2H), 2.71 (t, 1H), 2.88 (tt, 1H), 3.19 (t, 1H), 3.52 (dd, 2H), 3.90 (d, 1H), 4.71 (d, 1H), 6.51 (s, 1H), 7.00 (dd, 1H), 7.09-7.15 (m, 3H), 7.21 (t, 1H), 7.40 (t, 2H), 7.80 (d, 1H), 8.22 (bs, 1H), 8.24 (d, 1H), 8.28 (d, 1H), 8.84 (bs, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]2=[O:23])=[N:7]1.[OH-].[Na+]>C(OC(=O)C)(=O)C.O>[CH3:5][N:6]1[CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:12]2=[O:23])=[N:7]1
Reactant: O=[N+]([O-])O
Reactant: Cn1ccc(N2CCN(C(=O)OC(C)(C)C)C2=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)C2=O)n1
Reaction time: 0.08 h

Procedure:
To acetic anhydride (30 mL) was added fuming nitric acid (3.77 mL) under ice-cooling, and the mixture was stirred for 5 min. The obtained solution was added dropwise to a solution of tert-butyl 3-(1-methyl-1H-pyrazol-3-yl)-2-oxoimidazolidine-1-carboxylate (12.1 g) in acetic anhydride (60 mL) under ice-cooling, and the mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water, and the mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (11.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[NH:19][C:24]2=[S:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2c(N)c1OC
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc2ncnc3c2c(c1OC)NC(=S)N3c1cccc(Br)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of N4-(3-bromo-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (80 mg, 0.21 mmol) (from Example 6, Step B, supra) in 1,2-dichloroethane (50 mL) was added 1,1′-thiocarbonyldiimidazole (0.38 g, 2.13 mmol) (Fluka). The reaction mixture was heated with stirring at 90° C. for 4 hours. The solvents were evaporated and the residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:2:0.05) as eluent to give the desired 3-(3-bromo-phenyl)-8,9-dimethoxy-1H,3H-1,3,4,6-tetraaza-phenalene-2-thione as a yellow solid. (Yield 80 mg, 91%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([CH2:6][CH3:7])[CH2:4][OH:5].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:35](Cl)=[O:36]>O1CCCC1>[CH3:44][O:43][C:39]1[CH:38]=[C:34]([CH:33]=[C:32]([O:31][CH3:30])[C:40]=1[O:41][CH3:42])[C:35]([O:5][CH2:4][C:3]([N:2]([CH3:1])[CH3:13])([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH2:6][CH3:7])=[O:36]
Reactant: CCC(CO)(c1cccs1)N(C)C
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(c1cccs1)N(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
2-Dimethylamino-2-(2-thienyl)-1-butanol (8 g), triethylamine (4.85 g) and dimethylaminopyridine (catalytic amount) are dissolved in tetrahydrofuran (10 ml), and 3,4,5-trimethoxybenzoyl chloride (11.1 g) is gradually added to the solution under ice-cooling. The mixture is stirred at room temperature for 16 hours and concentrated under reduced pressure to remove solvent. The residue is dissolved in diluted hydrochloric acid, and the solution is washed with ether. The solution is alkalized with potassium carbonate and extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel column chromatography (solvent, n-hexane:ethyl acetate=5:2), whereby 2-dimethylamino-2-(2-thienyl)-butyl 3,4,5-trimethoxybenzoate (12.8 g) is obtained as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[C:12]([O:15][CH:16](OCC)OCC)(=O)[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:16][O:15][CH2:12][CH3:13])[C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: O=C1Cc2cc(Br)cnc2N1
Product: CCOC=C1C(=O)Nc2ncc(Br)cc21

Procedure:
This compound was synthesized from 5-bromo-1H-pyrrolo[2,3-b]pyridin-2-one and and diethoxymethyl acetate according to Procedure A. 1H NMR 400 MHz (DMSO-d6): δ11.02 (s, 1H); 8.07 (s, 1H); 7.88 (s, 1H); 7.71 (s, 1H); 4.40 (m, 2H); 1.34 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:24][CH3:25])[C:13]3[C:18]([C:19]=2[C:20]#[N:21])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=3)=[CH:7][CH:6]=1.CCN(CC)CC.[C:33](Cl)(=[O:35])[CH3:34]>C1COCC1>[C:20]([C:19]1[C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[CH:16][CH:17]=2)[N:12]([CH2:24][CH3:25])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][C:33](=[O:35])[CH3:34])=[CH:6][CH:7]=1)#[N:21]
Reactant: CC(=O)Cl
Reactant: CCn1c(-c2ccc(OCCN)cc2)c(C#N)c2ccc(OC)cc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1c(-c2ccc(OCCNC(C)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, step B, was dissolved in THF (400 μL), and Et3N (24 μL, 0.17 mmol). Acetyl chloride (10 μL, 0.14 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was dried and concentrated. Purification by silica gel chromatography (EtOAc) yielded N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl} acetamide (33 mg, 97%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[B:9]([OH:11])[OH:10])=O.[C-:12]#[N:13].[Na+].Cl>O>[C:12]([CH:1]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[B:9]([OH:10])[O:11]1)#[N:13]
Reactant: O=Cc1ccccc1B(O)O
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CC1OB(O)c2ccccc21
Temperature: 5 °C

Procedure:
2-formyl phenyl boronic acid (1.0 parts, 0.007M) was added to an aqueous solution of sodium cyanide (0.35 parts) in water (20 ml) at 20° C. with stirring. After 15 mins the reactants were cooled to 5° C. and carefully neutralised to pH 5 with concentrated hydrochloric acid. The resultant white precipitate was filtered and recrystallised from water (25,ml). The product was dried over calcium chloride. Yield=0.29 parts (26% theory) mp=114°-5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18]Br)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:20]#[N:21].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][C:20]#[N:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CBr)cc2C1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(CC#N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a solution of 21.76 mmol of tert-butyl-7-(bromomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in 80 ml DMF were added at 0° C. 65.3 mmol sodium cyanide in small portions. The mixture was stirred at room temperature for 2 h. Brine solution was added to the mixture and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and filtered. Evaporation of the solvent gave 5.6 g of a brown oil. The material was purified by flash chromatography to yield 1.63 g of a pale yellow solid (27.5%).