Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[C:11]([C:13]1[CH:14]=[C:15]2[CH:21]=[CH:20]N[C:16]2=NC=1)#[CH:12].C(N(CC)CC)C.CN(C=[O:33])C>[Cu]I.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>[NH2:10][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([C:20]#[C:21][C:15]2[CH:14]=[C:13]([OH:33])[CH:11]=[CH:12][CH:16]=2)=[C:6]([CH3:9])[N:5]=1
Reactant: C#Cc1cnc2[nH]ccc2c1
Reactant: Cc1nc(N)nc(Cl)c1I
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(Cl)c1C#Cc1cccc(O)c1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 500 mg (1.9 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 396 mg (2.8 mmol) 5-ethynyl-1H-pyrrolo[2,3-b]pyridine (A-20) using 35 mg (0.19 mmol) CuI, 130 mg (0.19 mmol) PdCl2(PPh3)2 and 2.6 mL (19 mmol) triethylamine in 6 mL dry DMF. The product precipitates from the reaction mixture, is filtered off and washed with DMF. Yield: 436 mg (75%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[CH2:13][NH:14][CH:15]1[CH2:17][CH2:16]1)([CH3:3])[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[CH2:13][N:14]([CH:15]1[CH2:16][CH2:17]1)[CH3:19])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)OC(=O)c1ccc(Br)cc1CNC1CC1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC(C)OC(=O)c1ccc(Br)cc1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
A solution of 4-bromo-2-cyclopropylaminomethyl-benzoic acid isopropyl ester (Intermediate 119, 1.33 g, 4.26 mmol) in acetone (8 mL) was treated with potassium carbonate (2.36 g, 17.05 mmol) and methyl iodide (0.53 mL, 8.52 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 h. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered over a short bed of silica gel (230-400 mesh) and evaporated in vacuo to afford the title product (1.23 g, 70%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=O.[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(C1C=CC=CC=1)(=O)C>O.C(O)C>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]=[CH:3][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])=[CH:7][CH:8]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccc(Br)cc1)c1ccccc1
Reaction time: 8 h
Yield: 93 %

Procedure:
Sodium hydroxide (1.88 g, 47 mmol) and 4-bromoacetophenone (7.47 g, 37.5 mmol) were dissolved in water (15 mL) and ethanol (50 mL). Benzaldehyde (4.00 g, 37.5 mmol) dissolved in ethanol (20 mL) was added dropwise to the acetophenone solution. A slurry quickly formed, which was allowed to stir overnight. The slurry was filtered, was with water until the filtrate was neutral to pH paper, and dried at 100° C. for 12 hours. A light tan solid was obtained (10.0 g, 93% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:36]/[O:37][CH3:38])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][N:33]=[C:29]4[N:28]=[C:27](OC)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.NC1SC=C(/C(=N/OC)/C(N[C@@H]2C(=O)N3[C@@H]2SCC(CSC2N4N=C(N)N=C4N=C(C)C=2)=C3[C:58]([OH:60])=[O:59])=O)N=1>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:36]/[O:37][CH3:38])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:58]([OH:60])=[O:59])[N:33]=[C:29]4[N:28]=[CH:27][CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(C)nc4nc(N)nn34)CS[C@H]12)c1csc(N)n1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(OC)nc4ncnn34)CS[C@H]12)c1csc(N)n1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3ccnc4nc(C(=O)O)nn34)CS[C@H]12)c1csc(N)n1

Procedure:
(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-methoxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Compound 17: (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-amino-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]#[N:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20]Br.O>CS(C)=O>[Cl:1][C:2]1[C:11]([C:12]2([C:13]#[N:14])[CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrCCCBr
Reactant: COC(=O)c1cccc(CC#N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CCC2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A solution (15 mL) of methyl 2-chloro-3-(cyanomethyl)benzoate (1.50, 7.16 mmol) produced in Example C61(iii) in dimethylsulfoxide was cooled at which the solution did not solidify, sodium hydride (60%, 869 mg, 21.7 mmol) was slowly added, and the mixture was stirred at room temperature for 30 min. To the suspension was added dropwise 1,3-dibromopropane (1.45 mL, 14.3 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was slowly added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→50/50) to give the title compound (714 mg, 40%) as a white powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:15][C@:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[CH:28][CH:27]=3)[CH:19]=2)([O:16][CH3:17])[C@H:13]([OH:38])[C@@H:12]([OH:39])[C@@H:11]1O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[CH3:51][OH:52]>CN(C=O)C.O>[CH2:51]([O:52][C@H:11]1[C@H:12]([O:39][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:13]([O:38][CH2:14][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]([F:35])([F:36])[F:37])=[CH:30][CH:31]=3)[CH:19]=2)([O:16][CH3:17])[O:15][C@@H:10]1[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:29]1[CH:28]=[CH:27][CH:26]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 7f (2.90 g, 4.78 mmol) was dissolved in 70 mL DMF and cooled to 0° C., followed by addition of 60% NaH (955 mg, 23.9 mmol). The reaction mixture was warmed and stirred for 1 hour at room temperature before benzyl bromide (3.0 mL, 23.9 mmol) was added. After stirring for 3 hours, 5 mL methanol and 10 mL water were added. The reaction mixture was partitioned after 100 mL water and 30 mL saturated sodium chloride solution were added. The aqueous phase was extracted with ethyl acetate (50 mL×3) and the organic extract was washed with saturated sodium chloride solution (30 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phen yl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 7g (4.60 g, pale yellow liquid), which was used directly in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].[C:22]1([CH2:28][CH2:29][CH2:30][C:31](Cl)=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:34](I)[CH3:35]>>[CH2:34]([N:1]1[C:2]2=[CH:3][C:4]3[C:5]([CH3:21])([CH3:20])[C:6](=[O:19])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]=3[CH:9]=[C:10]2[N:11]=[C:31]1[CH2:30][CH2:29][CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:35]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: CCI
Product: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(CCCc1ccccc1)n3CC
Yield: 12.6 %

Procedure:
1-Ethyl-7,7-dimethyl-5-pentyl-2-(3-phenyl-propyl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (36 mg) is synthesized from A8 (200 mg), freshly prepared 4-phenyl-butyryl chloride (150 mg; 0.82 mmol) and ethyl iodide (70 μl; 0.87 mmol) as described in Example 57.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([CH3:13])[N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.C(N(C(C)C)C(C)C)C>CC#N.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:13])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:6]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:7]=1
Reactant: COC(=O)c1c(C)nc(Cl)nc1Cl
Reactant: Cc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)nc(Cl)nc1Nc1cccc(C)c1
Yield: 96.8 %

Procedure:
A mixture of methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (940 mg, 4.25 mmol), m-toluidine (0.461 mL, 4.25 mmol) and N-ethyldiisopropylamine (1.481 mL, 8.51 mmol) in CH3CN (30 mL) was heated under reflux for 3 h. The mixture was diluted with EtOAc, and was washed with brine and water. The organic extract was dried and concentrated under reduced pressure to give the title compound as a light yellow solid (1.2 g, 97%). [M+H] calc'd for C14H14N3ClO2, 292; found, 292.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1([OH:25])[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:11])[CH2:2]2.[CH3:26][Br:27]>C(#N)C.C(Cl)(Cl)Cl>[Br-:27].[OH:25][C:12]1([C:10]([NH:9][CH:3]2[CH:4]3[CH2:5][CH2:6][N+:1]([CH3:26])([CH2:8][CH2:7]3)[CH2:2]2)=[O:11])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:19]2[C:24]1=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: O=C(NC1CN2CCC1CC2)C1(O)c2ccccc2-c2ccccc21
Reactant: CBr
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: C[N+]12CCC(CC1)C(NC(=O)C1(O)c3ccccc3-c3ccccc31)C2
Product: [Br-]
Temperature: 25 °C
Reaction time: 96 h

Procedure:
0.245 g (0.00073 mol) of N-(1-azabicyclo[2.2.2]oct-3-yl)-9-hydroxy-9H-fluorene-9-carboxamide (Example 41) were dissolved in 4 ml of acetonitrile and 6 ml of CHCl3. To this solution 5.46 ml of a 1 M solution of methyl bromide in acetonitrile were added and the mixture was stirred for 96 h at room temperature under N2 atmosphere. After this time the solvents were evaporated. The residue was coevaporated with ether three times. Ether was added to the residue and the mixture stirred. The solid obtained was filtered and washed several times with ether. The yield was 0.26 g (83.8%) of the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[C:49]3[C:48](=[O:50])[CH2:47][CH2:46][CH2:45][C:44]=3[N:43]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=3)[C:42](=[O:61])[N:41]2[CH2:62][C:63](O)=[O:64])=[CH:36][CH:35]=1)#[N:33].N>CN(C)C=O>[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[C:49]3[C:48](=[O:50])[CH2:47][CH2:46][CH2:45][C:44]=3[N:43]([C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:59])([F:60])[F:58])[CH:52]=3)[C:42](=[O:61])[N:41]2[CH2:62][C:63]([NH2:8])=[O:64])=[CH:36][CH:35]=1)#[N:33]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (38 mg, 100 μmol) and triethylamine (70 μL, 500 μmol) is added to a solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)acetic acid (example 32, 47 mg, 100 μmol) in N,N-dimethylformamide (0.5 mL). After 20 min ammonia (0.5 M in 1,4-dioxane, 200 μL, 100 μmol) is added, and the mixture is stirred at room temperature for 2 h and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 29 mg; ESI mass spectrum [M+H]+=469; Retention time HPLC: 0.84 min (Z018_S04).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:15])=[N:11][N:10]=1.[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1.C(N(CC)CC)C>CC(N(C)C)=O>[CH:29]1([CH2:32][N:26]2[CH2:27][CH2:28][N:23]([C:20]3[N:19]=[CH:18][C:17]([NH:16][C:14]([C:12]4[O:13][C:9]([NH:8][C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[N:10][N:11]=4)=[O:15])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[CH2:31][CH2:30]1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nnc(Nc2ccccc2F)o1
Reactant: BrCC1CC1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCN(CC3CC3)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Temperature: 110 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
5-[(2-Fluorophenyl)amino]-N-(6-piperazin-1-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (Intermediate 41) (120 mg, 0.31 mmol) in DMA (2 mL) was placed in a microwave tube with cyclopropylmethyl bromide (88 mg, 0.62 mmol), and triethylamine (64 mg, 0.62 mmol). The mixture was heated with stirring in the microwave at 110° C. for 60 minutes then transferred directly onto a reverse phase HPLC column and eluted with a gradient of acetonitrile/water containing 0.2%/TFA to give the title compound (125 mg, 91%) as a solid; 1H NMR δ 10.65 (1H, s), 10.40 (1H, bs), 8.20 (1H, s), 7.65 (2H, m), 6.90 (2H, m), 6.80 (1H, m), 6.65 (1H, d), 4.00 (2H, d), 3.25 (2H, d), 2.80 (6H, m), 0.75 (1H, m), 0.30 (2H, m), 0.00 (2H, m); MS m/e MH+ 438.
Reaction SMILES: CC(C)=O.[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCOC(C)=O>[CH2:27]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C1CCc2ccc(OCc3ccccc3)cc2O1
Yield: 85.7 %

Procedure:
To a 5 L acetone solution of ethyl 7-hydroxy-chromane-2-carboxylate (630.1 g, 2.84 mol) was added potassium carbonate powder (785 g, 5.68 mol) and benzyl bromide (405 ml, 3.41 mol). The resulting suspension was heated to reflux for 16 hr. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated to give solid material, which was re-dissolved in AcOEt, washed with water to remove residual salt, dried over MgSO4, filtered, concentrated to a small volume. Addition of hexanes caused precipitation of the title compound, which was collected by suction-filtration. The filtrate was triturated from dichloromethane-hexanes to give more precipitates. Finally the filtrate was concentrated and chromatographed on silica gel eluting with 20 to 80% dichloromethane/hexanes. Combination of all crops yielded the title compound 760.2 g as off-white solid (86%).
Reaction SMILES: [C:1](=[O:28])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[CH:11][N:10]=2)[CH2:5][CH2:4]1.[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>N1C=CC=CC=1>[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([C:1]([O:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[CH:11][N:10]=3)[CH2:7][CH2:8]2)=[O:28])[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: NC(=O)c1ccc(N2CCC(OC(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)nc1
Reactant: CC(C)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)OC2CCN(c3ccc(C(N)=O)cn3)CC2)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To the solution of 1-(5-carbamoylpyridin-2-yl)-piperidin-4-yl 4-nitrophenyl carbonate (3.0 g, 7.77 mmol) in pyridine (50 ml) was added 1-isopropylpiperazine (1.05 g, 8.16 mmol) and DIPEA (2.01 g, 15.5 mmol). The resulting mixture was stirred at 30° C. for 2 h before it was concentrated to dryness. The residue was further purified by silica gel chromatography (DCM: MeOH=50:1 to 5:1) to afford the title compound as a white solid (1.46 g, 50%). MP: 200.1-203.6° C. [1H NMR (DMSO, 500 MHz): δ 8.61 (d, J=2 Hz, 1H), 7.95 (dd, J=2.5 Hz, 9 Hz, 1H), 7.53 (s, 1H), 7.12 (s, 1H), 6.87 (d, J=9.5 Hz, 1H), 4.83 (m, 1H), 3.90-3.85 (m, 2H), 3.54-3.49 (m, 2H), 3.34 (s, 4H), 2.67-2.64 (m, 1H), 2.38 (m, 4H), 1.89-1.85 (m, 2H), 1.58-1.54 (m, 2H), 0.95 (d, J=6.5 Hz, 6H); LCMS RtA=1.61 min, [M+H]+=376.3].
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:11]1[C:23]2[CH:22]=[CH:21][C:20]([CH:24]=O)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([CH:26]=O)[CH:16]=2)[CH3:10]>C1(C)C=CC=CC=1.C1COCC1>[C:1]1([NH:7][N:8]=[CH:24][C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:11]([CH2:9][CH3:10])[C:12]2[CH:13]=[CH:14][C:15]([CH:26]=[N:8][NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:16][C:17]3=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCn1c2ccc(C=O)cc2c2cc(C=O)ccc21
Reactant: NNc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCn1c2ccc(C=NNc3ccccc3)cc2c2cc(C=NNc3ccccc3)ccc21
Temperature: 25 °C

Procedure:
Phenylhydrazine (0.2 mole, commercially available from Aldrich, Milwaukee, Wis.) and N-ethyl-3,6-diformylcarbazole (0.1 mole) were dissolved in 100 ml of a 1:1 v/v mixture of toluene and THF in 250 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was refluxed for 2 hours. Thin layer chromatography indicated the disappearance of the starting materials. At the end of the reaction, the mixture was cooled to room temperature. The N-ethyl-3,6-diformylcarbazole bis(N-phenylhydrazone) crystals formed upon standing were filtered off, washed with isopropanol and dried in a vacuum oven at 50° C. for 6 hours. Without further purification, the product was used for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[C:10]([OH:12])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:46][C:47]1[S:48][CH:49]=[C:50]([C:52]2[CH:63]=[CH:62][C:55]([C:56]([NH:58][CH:59]3[CH2:61][CH2:60]3)=[O:57])=[CH:54][CH:53]=2)[N:51]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[C:10](=[O:12])[NH:46][C:47]1[S:48][CH:49]=[C:50]([C:52]2[CH:53]=[CH:54][C:55]([C:56](=[O:57])[NH:58][CH:59]3[CH2:61][CH2:60]3)=[CH:62][CH:63]=2)[N:51]=1)=[O:4]
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCC[C@@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reaction time: 0.25 h

Procedure:
Rac-cis-cyclopentane-1,2-dicarboxylic acid monomethyl ester (172 mg) was dissolved in DMF (5 mL) and treated with HATU (1.1 eq. 470 mg) and DIEA (3 eq, 500 μL) and stirred for 15 minutes. Then 4-(2-amino-thiazol-4-yl)-N-cyclopropyl-benzamide (1 eq, 260 mg) was added and the mixture stirred at ambient temperature overnight. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the product. MS: 414.5.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:24](OCC)=[O:25].[CH3:29][O:30][CH2:31][CH2:32][NH2:33].C(N(C(C)C)CC)(C)C>C(Cl)CCl.ClCCl>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[C:14]([NH:13][C:8]1[C:7]2[N:6]=[CH:5][C:4]3[C:24](=[O:25])[N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH2:2][C:3]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:23]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CBr
Reactant: COCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COCCN1Cc2c(cnc3c(NC(=O)c4c(Cl)cccc4Cl)cccc23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A mixture of 4-bromomethyl-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (100 mg), 2-methoxyethylamine (18.7 mg) and N,N-diisopropyl-N-ethylamine (134 mg) in ethylene chloride (1 ml) was stirred for 2 hours at ambient temperature. The mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (methanoldichloromethane) to give 6-(2,6-dichlorobenzoylamino)-2,3-dihydro-2-(2-methoxyethyl)-1H-pyrrolo-[3,4-c]quinolin-3-one (76 mg).
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]([OH:5])=[O:4].[N+](=[CH2:19])=[N-].C(Cl)(Cl)Cl>CCOCC>[CH3:19][O:4][C:3](=[O:5])[C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: C=[N+]=[N-]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)[C@H](C)CCC[C@H](C)CCCC(C)C

Procedure:
2(R),6(R),10-trimethylundecanoic acid (270 mg., [α]D25 -8.64°) was dissolved in ether and treated with an excess of etheral solution of diazomethane at 23° C. for 2.0 hour. The crude product was subjected to evaporative distillation at 98°-101°/0.15 mm Hg to give 247 mg. of 2(R), 6(R),10-trimethylundecanoic acid methyl ester as a colorless oil, [α]D25 -11.30° (c1.1065, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35]1>>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:29][C:30]([NH:33][CH:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35]1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)NCC2
Reactant: NC1Cc2ccccc2C1
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1OC)N(CC(=O)NC1Cc3ccccc3C1)CC2

Procedure:
prepared by reaction of 1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-ammo-indane