Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].C([Li])(CC)C.[P:16](Cl)([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[CH3:6][O:5][P:4]([CH:3]([P:16](=[O:17])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH:2]([CH3:10])[CH3:1])(=[O:9])[O:7][CH3:8]
Reactant: CCOP(=O)(Cl)OCC
Reactant: COP(=O)(CC(C)C)OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C(C)C)P(=O)(OC)OC
Reaction time: 0.5 h

Procedure:
To a solution of 2--methylpropylphosphonic acid, dimethyl ester (2.20 g, 14.47 mmol) in anhydrous THF (200 ml) is added sec-butyllithium (20.04 ml, 26.05 mmol, 1.3M in cyclohexane) at 0° C. Following the addition, stirring is continued for an additional 30 minutes. This solution is then slowly added to a solution of diethyl chlorophosphate (2.50 9, 14.47 mmol) in anhydrous THF (100 ml) at room temperature. After stirring the reaction overnight, the mixture is quenched by the addition of a saturated aqueous solution of sodium bicarbonate and then extracted with methylene chloride. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography with 30% acetone in hexanes on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH3:10][CH:11]([CH3:22])[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[C@H:13]([CH2:12][CH:11]([CH3:22])[CH3:10])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)COC(=O)C(=O)CC(C)C
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CC(C)COC(=O)[C@H](CC(C)C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and iso-butyl 4-methyl-2-oxopentanoate (prepared by following General Procedure AO above using 4-methyl-2-oxovaleric acid (Fluka) and iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.6 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>>[N+:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[CH3:1])[C:6]#[N:7])([O-:12])=[O:11]
Reactant: Cc1ccc(C#N)cc1
Reactant: O=[N+]([O-])O
Product: Cc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
399 g (2.56 mol) of 4-methylbenzonitrile were added over the course of 90 min into 1 l of fuming nitric acid at -10° C. 1 h after the addition, the mixture was poured into 2.5 l of ice-water, whereupon a solid precipitated and was separated off on a suction filter funnel and washed to neutral pH with water. The yield was 363 g (88%). 1H-NMR (CDCl3 ; δ in ppm): 8.3 (d,1H); 7.8 (dd, 1H); 7.5 (dd, 1H); 2.7 (s, 3H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:31][CH:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)[CH:12]=3)[CH:7]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Reactant: CN1CCC(N)CC1
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC3CCN(C)CC3)cc21
Temperature: 180 °C
Yield: 19.5 %

Procedure:
To a solution of Example A3 (2.1 g, 5.96 mmol) in NMP (10 mL) was added 1-methyl-piperidin-4-ylamine (1.36 g, 11.9 mmol) and DBU (1.7 g, 11.4 mmol). Nitrogen was bubbled through the mixture for 5 min and then it was heated at 180° C. for 12 h. The reaction mixture was cooled to RT, poured into water and extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to yield 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpiperidin-4-ylamino)-1,6-naphthyridin-2(1H)-one (0.50 g, 19.5% yield) which was 70% pure (30% de-methylated by-product) and used without further purification.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[NH2:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:25][OH:26])[S:18][C:17]=1[C:28]([NH2:30])=[O:29].[C:31]1(O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[NH2:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:25][O:26][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:18][C:17]=1[C:28]([NH2:30])=[O:29]
Reactant: Cc1cc(CO)c2c(N)c(C(N)=O)sc2n1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(COc2ccccc2)c2c(N)c(C(N)=O)sc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.8 %

Procedure:
Diisopropyl azodicarboxylate (DIAD) (14 mg, 0.069 mmol) was added to a solution of 3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (15 mg, 0.063 mmol), phenol (6 mg, 0.069 mmol), and Ph3P (18 mg, 0.069 mmol) in THF (1.5 mL) at 0° C. The mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was concentrated and fractionated by preparative TLC (10% MeOH/CH2Cl2) providing the title compound (12 mg, 61%) as an orange solid, m.p. 194-196° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:27])[C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[C:39]3([CH2:44][CH2:43][CH2:42][NH:41][CH2:40]3)[C:38](=[O:45])[N:37]([CH3:46])[CH2:36]2)=[CH:31][CH:30]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC#N.C(=O)(O)[O-].[Na+].C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:27])[C:16]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:18])[CH3:17])[C:11]([N:41]1[CH2:42][CH2:43][CH2:44][C:39]2([C:38](=[O:45])[N:37]([CH3:46])[CH2:36][CH:35]2[C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)[CH2:40]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CC(c2ccc(F)cc2)C2(CCCNC2)C1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CN1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Reaction time: 20 h
Yield: 96.7 %

Procedure:
To a stirred solution of (R)-3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methylpropionylamino)-propionic acid (Intermediate 3A) (344 mg, 0.904 mmol) and 4-(4-fluorophenyl)-2-methyl-2,7-diazaspiro[4.5]decan-1-one (270 mg, 0.904 mmol) in MeCN (4 mL) was added dropwise a solution of ®T3P (50% in EtOAc) (1.055 ml, 1.807 mmol) at room temperature. The resulting colourless solution was stirred for 20 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL). The aqueous phase was separated and extracted using DCM (3×10 mL), the combined organic fractions were washed with 10% citric acid (10 mL), dried (MgSO4) and then concentrated under reduced pressure to afford tert-butyl 1-((2R)-3-(benzyloxy)-1-(4-(4-fluorophenyl)-2-methyl-1-oxo-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (546 mg, 97%) as a white amorphous solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[C:32]([Br:35])[CH:31]=[CH:30][C:29]=5[F:36])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38].CCOCC>C(Cl)Cl>[ClH:38].[ClH:38].[ClH:38].[Br:35][C:32]1[CH:31]=[CH:30][C:29]([F:36])=[C:28]2[C:33]=1[CH:34]=[C:25]([C:23]1[C:22]([NH2:37])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=1)[N:26]=[CH:27]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5c(Br)ccc(F)c5cn4)c3)cn2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Br)ccc(F)c2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-{4-[6-amino-5-(5-bromo-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (82 mg, 0.14 mmol) in DCM (3.0 mL) was added 1.0 M of HCl in Et2O (3.0 mL, 3.0 mmol), and the mixture was stirred at ambient temperature for 1 h. Almost immediately a pale yellow solid precipitated. The solvents were evaporated, and the residue was transferred into a vial and dried in vacuo overnight, yielding the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.09-2.28 (m, 4H), 3.03-3.16 (m, 2H), 3.39 (dd, J=13.8, 1.9 Hz, 2H), 4.47-4.58 (m, 1H), 7.61 (dd, J=9.8, 8.4 Hz, 1H), 8.12 (s, 1H), 8.23-8.32 (m, 2H), 8.42 (s, 1H), 8.46 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H), 9.01 (br. s., 1H), 9.16 (br. s., 1H), 9.65 (s, 1H). MS (ES+): m/z=466.73/468.63 [MH+]. HPLC: tR=1.88 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[NH:10][CH:9]=[N:8][C:7]=2[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]=1[CH3:20]>>[CH3:1][N:10]1[C:11](=[O:13])[C:12]2[C:4]([CH3:3])=[C:5]([CH3:20])[N:6]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=[CH:9]1
Reactant: Cc1c(C)n(-c2ccccc2)c2nc[nH]c(=O)c12
Reactant: CI
Product: Cc1c(C)n(-c2ccccc2)c2ncn(C)c(=O)c12
Yield: 62.4 %

Procedure:
The starting material was prepared as described in Example 3 by the alkylation with methyl iodide of 5,6-dimethyl-7-phenyl-3H,7H-pyrrolo-[2,3-d]pyrimidin-4-one (see US Patent 4,229,453). There was thus obtained 3,5,6-trimethyl-7-phenyl-3H-7H-pyrrolo-[2,3-d]pyrimidin-4-one (62.4% yield) m.p. 207°-208° C.; microanalysis, found: C, 71.0; H, 6.2; N, 16.3%; C15H15N3 requires C, 71.1; H, 5.97; N, 16.6%; NMR: CDCl3 ; 2.1(3H, s, CH3), 2.4-2.5(3H, s, CH3), 3.5-3.6(3H, s, N-CH3), 7.25-7.6(5H, complex, aromatic), 7.7-7.8(1H, s, C-H).
Reaction SMILES: [C:1]([CH:5]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18]3=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:25][CH3:26])=[CH:9][C:8]=1[CH2:27][CH:28]=[CH2:29])([O:3]C)=[O:2].[OH-].[Na+].Cl>CO>[C:1]([CH:5]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18]3=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:25][CH3:26])=[CH:9][C:8]=1[CH2:27][CH:28]=[CH2:29])([OH:3])=[O:2]
Reactant: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1OC(C(=O)OC)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1OC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 0.141 g (0.30 mmol) of the product of Step H dissolved in 2.0 mL of methanol was added 0.25 mL of a 1.0N solution of sodium hydroxide and the reaction was stirred at room temperature for 2 hours. The reaction mixture was then adjusted to pH 7 with 1.0N hydrochloric acid and then partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), filtered, evaporated and then purified on a silica gel flash chromatography column eluted with chloroform-methanol-conc. ammonium hydroxide (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.092 g (69%) of the title compound as a white amorphous solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:13][C@@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:15]1([C@H:14]([N:21]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([F:12])([F:11])[F:1])[CH3:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: C[C@@H](N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](N=C(c1ccccc1)C(F)(F)F)c1ccccc1
Yield: 100.1 %

Procedure:
A solution of 2,2,2-trifluoroacetophenone (7.0 g, 40 mmol), R-(+)-α-methylbenzylamine (7.75 mL, 60 mmol), and p-toluenesulfonic acid monohydrate (0.77g, 4.0 mmol) in toluene (40 mL) was refluxed for 18 hours with a Dean-Stark trap. After cooling, the reaction mixture was diluted with toluene (50 mL), washed with 5% NaOH (1×50 mL), saturated NH4Cl (4×30 mL) and brine, dried over MgSO4, concentrated and dried at room temperature in vacuum to give the title compound as pale yellow liquid (11.1 g).
Reaction SMILES: [C:1]([C:5]1[CH:63]=[CH:62][C:8]([C:9]([NH:11][C@@H:12]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[N:47]=[CH:46][C:45]([C:48]4[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[CH:50][CH:49]=4)=[CH:44][N:43]=3)=[CH:38][CH:37]=2)[C:13]([NH:15][C@H:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17][C:18]([O:20]CC2C=CC=CC=2)=[O:19])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:31]([O:30][C:28](=[O:29])[C@@H:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:63][CH:62]=1)[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[N:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[CH:50][CH:49]=3)=[CH:44][N:43]=2)=[CH:40][CH:41]=1)[CH2:17][C:18]([OH:20])=[O:19])([CH3:32])([CH3:33])[CH3:34]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)N[C@@H](CC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)cc3)nc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
Prepared using General Procedures 18: To 4-benzyl 1-(tert-butyl) ((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-aspartate (50 mg, 0.058 mmol) in THF (2 mL) was added 10% Pd/C (10 mg). The reaction vessel was flushed with hydrogen gas and the reaction was stirred vigorously under hydrogen for 2 h at room temperature. The reaction mixture was filtered to remove the catalyst and the solvent was removed to give 38 mg (86%) of (S)-4-(tert-butoxy)-3-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoic acid INT-31 as a white solid. LCMS-ESI (m/z) calculated for C45H56N4O7: 764.4. found 765.4 [M+H]+, tR=4.24 min (Method 16).
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)\[CH2:5][CH3:6].[N+](=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Cl:1][CH2:2][CH:3]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]1([CH2:5][CH3:6])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: CC/C(=C\CCl)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1C(CCl)C1(CC)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.3 %

Procedure:
To a solution of 1-[(E)-3-chloro-1-ethyl-1-propenyl]-3-nitrobenzene (Preparation 15, 50 g, 0.22 mol) in dichloromethane (40 ml) was added rhodium (II) acetate dimer (2.0 g, 4.6 mmol). To the mixture was added dropwise at room temperature over 6 hours a solution of ethyl diazoacetate (50 ml, 54.25 g, 0.475 mol) in dichloromethane (50 ml), then the mixture stirred at room temperature for 16 hours. To the mixture was added dropwise at room temperature over 7 hours a solution of ethyl diazoacetate (20 ml, 21.70 g, 0.190 mol) in dichloromethane (20 ml), then the mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and the residue purified by silica column (1 kg) chromatography, eluting with 1:1 hexane/dichloromethane. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale orange oil (10.5 g, 15%).
Reaction SMILES: [Cl-].Cl[C:3](Cl)=[N+:4]([CH3:6])[CH3:5].[CH2:8]([N:13]1[C:21]2[N:20]=[CH:19][NH:18][C:17]=2[C:16](=[O:22])[NH:15]/[C:14]/1=[N:23]/[NH2:24])[CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>C(Cl)Cl>[CH3:5][N:4]([CH3:6])[C:3]1[N:15]2[C:16](=[O:22])[C:17]3[NH:18][CH:19]=[N:20][C:21]=3[N:13]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]2=[N:23][N:24]=1
Reactant: CCCCCn1/c(=N\N)[nH]c(=O)c2[nH]cnc21
Reactant: C[N+](C)=C(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(N(C)C)nnc12
Reaction time: 0.08 h
Yield: 69.1 %

Procedure:
To methylene chloride (10 mL) was added [B] N-(dichloromethylene)-N-methylmethanaminium chloride (0.21 g, 1.3 mmol). After stirring for 5 mins, (2Z)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (0.10 g, 0.42 mmol) was added, and the mixture was stirred at rt for 5 hrs. LCMS analysis showed product as a major peak was formed. 1N NaOH was carefully added to neutralize the acid, and the mixture was extracted with methylene chloride three times. The combined organic layers were dried by MgSO4, filtered and concentrated in vacuo to yield the desired product (84 mg, 69%). LCMS calculated for C13H20N7O (M+H): 290.2. found 290.1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[I:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(I)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(Cc1ccccc1)c1cccc(I)c1

Procedure:
m-Iodobenzoic acid (1 g, 0.004 mol) was dissolved in MeCN (20 ml), Cs2CO3 (2.63 g, 2 eq) and benzyl bromide (0.528 ml, 1.1 eq) added. The mixture was heated at reflux overnight. The mixture was concentrated, taken up in EtOAc, washed with water, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc in hexane) to give 1.6 g of M16-3.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]#[N:9].[CH3:16][S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(=[O:19])=[O:18]>C(O)C>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:23]1[CH2:24][CH2:25][N:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:21][CH2:22]1)=[NH:9]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: N#CNc1ccccc1-c1ccccc1
Solvent: CCO
Product: CS(=O)(=O)N1CCN(C(=N)Nc2ccccc2-c2ccccc2)CC1

Procedure:
A mixture of 2-biphenylylcyanamide (3.8 g), 1-methanesulphonylpiperazine (3.8 g) and ethanol (60 ml) was heated at 90°-95° C. for 12 hours to give N-(2-biphenylyl)-4-methanesulphonylpiperazine-1-carboxamidine (m.p. 178°-180° C.) which was recrystallized from ethanol.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]1([CH2:20][NH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O>C1C=CC=CC=1>[C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([NH:21][CH2:20][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC1CCCCC1
Reactant: O=C1CCC(c2ccccc2)CC1
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(C2CCC(NCC3CCCCC3)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of 5 g of 4-phenylcyclohexanone and cyclohexylmethylamine in 100 ml of benzene was refluxed for 2 hours with removing water and the solvent was distilled away in vacuo. The residue was dissolved in methanol and to the solution was added 1.5 g of sodium borohydride. The mixture was stirred at room temperature and the solvent was distilled away in vacuo. To the residue was added water and extracted with diethyl ether. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled away to give 7 g of N-(4-phenylcyclohexyl)-N-cyclohexylmethylamine as an oil. (N-(4-phenylcyclohexyl)-N-cyclohexylmethylamine hydrochloride, melting at 267°-270° C. with decomposition)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[C:12](Cl)(=[O:15])[CH2:13][CH3:14].Cl>C(Cl)(Cl)(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([O:8][CH3:9])=[C:6]([C:12](=[O:15])[CH2:13][CH3:14])[CH:7]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(Cl)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(=O)c1cc(Cl)c(OC)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A mixture of 2.01 g of 1-chloro-2,4-dimethoxybenzene and 1.08 g of propionyl chloride in 20 ml of CCl4 is cooled to 0° C., and a solution of 1.3 ml of TiCl4 in 7 ml of CCl4 is added dropwise. The reaction mixture is left stirring for 2 hours while the temperature is allowed to rise to r.t. It is poured into a mixture of concentrated HCl and ice, the resulting mixture is extracted with DCM, the organic phase is dried over magnesium sulphate and the solvents are evaporated off under vacuum. The residue is chromatographed on silica H, eluting with a DCM/heptane (80:20; v/v) mixture. 1.14 g of expected product, m.p.=115° C., are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[OH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:24]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([OH:21])[CH:23]=4)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: COc1ccc(B(O)O)cc1O
Product: COc1ccc(-c2cc3[nH]c4ccc(O)cc4c3c3c2C(=O)NC3=O)cc1O
Yield: 51 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 3-hydroxy-4-methoxybenzeneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(3-hydroxy-4-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (10) (1, Ar=3-hydroxy-4-methoxyphenyl) (51%), mp 265° C. (dec). 1H NMR δ [(CD3)2SO] 11.67 (s, 1H), 10.96 (s, 1H), 9.22 (s, 1H), 9.15 (s, 1H), 8.33 (d, J=2.4 Hz, 1H), 7.57 (s, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.06–6.99 (m, 2H), 6.85 (d, J=8.1 Hz, 1H), 3.81 (s, 3H). EIMS found M+: 374.0900. C21H14N2O5 requires 374,0903.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:20]([NH2:22])=[O:21].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:22][C:20](=[O:21])[C@@H:19]([NH:18][C:15]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:17])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Reactant: N#Cc1ccc(-c2ccc(C[C@H](N)C(N)=O)cc2)cc1
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: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(N)=O)CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-(tert-Butoxycarbonylamino)tetrahydro-2H-pyran-4-carboxylic acid (374 mg), (S)-2-amino-3-(4′-cyanobiphenyl-4-yl)propanamide (Example 3, step (iii), 405 mg) and N-ethyl-N-isopropylpropan-2-amine (0.664 mL) were dissolved in DMF (10 mL) and to the solution was added TBTU (734 mg). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated to dryness, dissolved in dichloromethane (20 mL) and was absorbed onto silica. The product was purified by chromatography on silica eluting with 20% ethyl acetate in isohexane, then 50% ethyl acetate in isohexane and then 100% ethyl acetate to afford after evaporation of the relevant fractions the sub-titled compound (700 mg).