Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])[C:17]=3[CH:29]=2)[C:3]1=[O:30].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([CH3:27])([CH3:28])[C:22]([OH:24])=[O:23])[C:17]=3[CH:29]=2)[C:3]1=[O:30]
Reactant: CCOC(=O)C(C)(C)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(C)(C)C(=O)O)c3c2)c1=O

Procedure:
To a solution of ethyl 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-α,α-dimethyl-1,2-benzisothiazole-3-acetate (6.30 g, 0.0143 mol) in methylene chloride at 0° C. is added boron tribromide in methylene chloride (1.0 M, 100 ml, 0.100 mol) such that the temperature does not exceed 15° C. The resultant mixture is stirred one hour at ambient temperature, quenched with 3 N hydrochloric acid, and diluted with methylene chloride. The organic layer is separated, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound as an off-white solid (mp 155-156° C.) which is identified by NMR and IR spectral analyses.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:37](=[O:36])[CH2:38][OH:39])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f26) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]([C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[NH:12][CH:13]=[O:14])=[O:2]>C1COCC1.[OH-].[OH-].[Pd+2]>[NH2:9][C:8]1[C:3]([CH:1]=[O:2])=[C:4]([NH:12][CH:13]=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=CNc1cccc([N+](=O)[O-])c1C=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cccc(NC=O)c1C=O
Reaction time: 4 h
Yield: 90.7 %

Procedure:
N-(2-Formyl-3-nitrophenyl)formamide (5a, 51.6 g, 0.27 mol) was dissolved in THF (1 L) and 20 wt % Pd(OH)2 on activated charcoal (4.96 g) was added. Hydrogenation was carried out at 37° C. in an oil bath under H2 atmosphere. After being stirred for 4 h, an additional 20 wt % Pd(OH)2 on activated charcoal (2.01 g) was added and the hydrogenation was continued further at 37° C. in an oil bath. After 22 h, the mixture was filtered and the Pd catalyst separated was washed with THF. The combined filtrate and washing were concentrated under reduced pressure. The generated crude solid was suspended in H2O (500 mL) and then the orange powder was collected by filtration, washed with H2O, and dried under vacuum to obtain N-(3-amino-2-formylphenyl)-formamide (7a, 40.2 g, 92%); 1H NMR (270 MHz) δ (CD3OD): rotamer A (major)* 6.53 (d, J=7.9 Hz, 1H), 6.66 (d, J=7.9 Hz, 1H), 7.17 (t, J=7.9 Hz, 1H), 8.23 (s, 1H), 9.97 (s, 1H); rotamer B (minor)* 6.33 (d, J=7.9 Hz, 1H), 6.54 (d, J=7.9 Hz, 1H), 7.17 (t, J=7.9 Hz, 1H), 8.40 (s, 1H), 10.05 (s, 1H). The ratio of two rotamers A and B is approximately 2:1.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:8]=2[CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][C:5]1=[O:26])(=[O:3])[CH3:2].[O:27]1CCCC1>Cl>[C:1]([NH:4][CH2:13][CH2:12][CH2:11][C:10]([C:9]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:8]=1[CH:7]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:6][C:5]([OH:27])=[O:26])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCC(=O)c2ccc(Cl)cc2C(c2ccccc2)CC1=O
Reactant: C1CCOC1
Agent: Cl
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1C(CC(=O)O)c1ccccc1

Procedure:
A solution of 3.30 g (0.009 mol) of 4-acetyl-11-chloro-1-phenyl-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione in 40 ml of tetrahydrofuran and 20 ml of 2N hydrochloric acid is stirred at room temperature for two days. Then, the solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with hexane-ethyl acetate (1:1) and crystallization from ethyl acetate/hexane gives 2-(4-acetamidobutyryl)-5-chloro-β-phenylhydrocinnamic acid as white crystals with melting point 114°-116°.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[N:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:5]=1)(O)=[O:2].S(Cl)([Cl:27])=O>CN(C)C=O>[Cl:27][C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[N:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:5]=1)=[O:2]
Reactant: COc1ccc2c(C(=O)O)cn(-c3ccnc4ccccc34)c2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)Cl)cn(-c3ccnc4ccccc34)c2c1

Procedure:
30 cm3 of sulphinyl chloride and one drop of dimethylformamide are added, at a temperature in the region of 22° C. and under an argon atmosphere, to 2.4 g (7.52 mmol) of 3-carboxy-6-methoxy-1-(quinol-4-yl)-1H-indole. After stirring at reflux for 16 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give 2.5 g of 3-chlorocarbonyl-6-methoxy-1-(quinol-4-yl)-1H-indole in the form of a yellow solid which is used directly in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].CC(O)=O.S(=O)(=O)(O)O.C1C(=O)N([I:27])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:27])=[CH:4][C:3]=1[F:10]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(F)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(Cl)c(F)cc1I
Yield: 70.4 %

Procedure:
A round-bottom flask was charged with 2-chloro-1-fluoro-4-methoxybenzene (Alfa Aesar, Ward Hill, Mass., 2.714 g, 16.90 mmol), DCM (24.86 ml), AcOH (24.86 ml), and sulfuric acid (0.496 ml, 9.30 mmol) to give a solution. n-iodosuccinimide (3.80 g, 16.90 mmol) was added in a single portion. TLC showed what appeared to be conversion of the starting material to a slightly higher, move UV-active spot. The mixture was diluted with DCM, washed with water (2×), washed with saturated aq. sodium thiosulfate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 0-10% EtOAc/Heptane) to give 3.409 g of a clear oil. This oil was used directly in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([NH:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][C:3]=1[C:12]([O:14]C)=O.[OH-].[Li+].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.[NH2:51][CH2:52][C:53]1[C:54]([F:70])=[C:55]([O:60][C:61]2[CH:62]=[C:63]([CH:66]=[C:67]([Cl:69])[CH:68]=2)[C:64]#[N:65])[C:56]([Cl:59])=[CH:57][CH:58]=1>C1COCC1.O.CN(C=O)C>[Cl:1][C:2]1[C:6]([C:7]([NH:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][C:3]=1[C:12]([NH:51][CH2:52][C:53]1[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([O:60][C:61]2[CH:62]=[C:63]([C:64]#[N:65])[CH:66]=[C:67]([Cl:69])[CH:68]=2)[C:54]=1[F:70])=[O:14]
Reactant: CCNC(=O)c1c[nH]c(C(=O)OC)c1Cl
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1c[nH]c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)c1Cl
Temperature: 35 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
To a solution of methyl 3-chloro-4-[(ethylamino)carbonyl]-1H-pyrrole-2-carboxylate (0.03 g, 0.130 mmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide (0.031 g, 1.301 mmol). The reaction mixture was stirred overnight at 35° C. The solvent was evaporated and the resulting solid placed under high vacuum. To the intermediate mixture was added DMF (1 mL), HATU (0.059 g, 0.156 mmol), DIPEA (0.034 ml, 0.195 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.040 g, 0.130 mmol). The solution was stirred for 2 h at RT. Purification was accomplished by HPLC. The desired fractions were neutralized with saturated sodium bicarbonate, extracted with EtOAc (3×5 mL), the organic layers combined, dried over sodium sulfate, filtered and evaporated to afford 3-chloro-N2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-N4-ethyl-1H-pyrrole-2,4-dicarboxamide (0.0033 g, 5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.15 (br. s., 1H) 8.14 (s, 1H) 7.83 (d, 2H) 7.44-7.54 (m, 4H) 7.37 (s, 1H) 4.57 (d, 2H) 3.20 (dd, 2H) 1.08 (t, 3H). MS: m/z 509.2 (M+1).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([C:45]([NH:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)=[O:46])=[N:25][C:26]=2[NH:30][CH2:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:33]1([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:31][NH:30][C:26]2[N:25]=[C:24]([C:45]([NH:47][CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)=[O:46])[N:23]=[C:22]3[C:27]=2[N:28]=[CH:29][N:21]3[C@H:6]2[C@H:5]([OH:4])[C@H:9]([OH:10])[C@@H:8]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=3)[O:7]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(C(=O)NCCN5CCCCC5)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(C(=O)NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)n1
Yield: 76.3 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[6-[(2,2-diphenylethyl)amino]-2-({[2-(1-piperidinyl)ethyl]amino}carbonyl)-9H-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3-furanyl acetate (Preparation 27) (230 mg, 0.31 mmol) and sodium carbonate (130 mg, 1.23 mmol) in methanol (15 ml) and water (1.5 ml) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was partioned between ethyl acetate (50 ml) and water (10 ml). The organic layer was washed with brine (10 ml), dried (anhydrous sodium sulphate) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume) gradually changing to dichloromethane:methanol:0.88 concentrated aqueous ammonia (93:7:0.7 by volume). Product containing fractions were evaporated and the resulting solid triturated with ether, filtered and dried to afford the title compound as a white powder (158 mg).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([NH:9][C:10]([NH:21][CH3:22])=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)#[N:8]>O>[C:7]([NH:9][C:10]([NH:21][CH3:22])=[N:11][CH2:12][CH2:13][S:14]([CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:2])#[N:8]
Reactant: CNC(=NCCSCc1nccs1)NC#N
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CNC(=NCCS(=O)Cc1nccs1)NC#N
Reaction time: 1 h
Yield: 100.7 %

Procedure:
Sodium metaperiodate (220 mg, 1.03 m.mol) was added to a stirred solution of N-cyano-N'-methyl-N"-[2-((2-thiazolyl)methylthio)ethyl]guanidine (255 mg, 1.0 m.mol) in water (90 ml). After 1 hour at 25° then 17 hours at 5° t.l.c. indicated the reaction was essentially complete. The solution was evaporated under reduced pressure at 60° to dryness, with azeotroping with n-propanol (2×). The residue was boiled with isopropanol (20 ml) for 3 minutes, filtered hot from 205 mg of inorganic salts, (100%), and evaporated under reduced pressure to a clear glass which was stirred continuously for 4 days under ether to give crude product (273 mg, 100%) m.p. 110° (softens only). Purification was effected by dissolution in acetonitrite (15 ml) and dilution of the filtered warm solution with ether to 220 ml. After 17 hours standing the precipitate had crystallised yielding, after filtration and washing with ether, N-cyano-N'-methyl-N" -[2-((2-thiazolyl)methylsulphinyl)ethyl]guanidine, (335 mg), m.p. 112°-113°C. Found: C, 39.62; H, 5.03; N, 25.64%. C9H13N5OS2 requires: C, 39.83; H, 4.83; N, 25.81%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:23])[C:15]2([CH:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:40])=[C:34](F)[C:35]=3[O:37][CH3:38])[C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28]2)[CH2:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:23])[C:15]2([CH:18]3[CH2:22][CH2:21][N:20]([C:34]4[C:35]([O:37][CH3:38])=[C:36]5[C:31]([C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28][N:27]5[CH:24]5[CH2:26][CH2:25]5)=[CH:32][C:33]=4[F:40])[CH2:19]3)[CH2:16][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1(C2CCNC2)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(N2CCC(C3(N(C)C4CCN(C(=O)OC(C)(C)C)CC4)CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 75 °C
Yield: 55 %

Procedure:
A solution of 4-[methyl-(1-pyrrolidin-3-yl-cyclopropyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.31 mmol) in acetonitrile (30.0 mL) was added 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (98 mg, 0.33 mmol) and DBU (0.23 mL, 1.53 mmol). The suspension was heated to 75° C. overnight. The reaction mixture was partitioned between ethyl acetate and 5% citric acid. The separated organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (10% methanol in dichloromethane) to give the title compound as a yellow solid (102 mg, 62%). ESI MS m/z 599.3 (M+H+).
Reaction SMILES: C(N(CC)CC)C.C(O[C@@H:12]1[C@H:18]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH2:16][CH3:17])[C:14](=[O:32])[CH2:13]1)[C:27]1[CH:26]=[CH:25][C:24]([OH:31])=[CH:23][C:22]=1[CH2:21][CH2:20]3)(=O)C.O>CCO>[OH:31][C:24]1[CH:25]=[CH:26][C:27]2[C@@H:28]3[C@H:19]([C@H:18]4[C@@:15]([CH2:30][CH2:29]3)([CH2:16][CH3:17])[C:14](=[O:32])[CH:13]=[CH:12]4)[CH2:20][CH2:21][C:22]=2[CH:23]=1
Reactant: CC[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1[C@@H](OC(C)=O)CC2=O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C=CC2=O
Temperature: 25 °C
Yield: 63.7 %

Procedure:
Triethylamine (0.5 ml, 3.6 mmol) was added to a suspension of 15α-acetoxy-3-hydroxy-18-methyl-estra-1,3,5(10)-trien-17-one (0.52 g, 1.5 mmol) in EtOH (7 ml). The mixture was heated under reflux for 2 h, cooled to room temperature and then water (30 ml) was added. The mixture was extracted with ethyl acetate (30 ml), the organic layer was washed with water (50 ml), dried and the solvent removed. The crude product was purified by flash chromatography on silica gel eluting with diisopropyl ether to afford pure 3-hydroxy-18-methyl-estra-1,3,5(10),15-tetraen-17-one (0.27 g, yield: 64%).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][NH:30][CH3:31].O>O1CCOCC1.ClCCl>[CH3:29][N:30]([CH2:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:31]
Reactant: CNC
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CN(C)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A 6 g portion of 2-chloromethyl-1,4-bis(phenylmethyl)piperazine was dissolved in 20 ml of dioxane. To this was added 3.14 g of potassium carbonate and 68 ml of 40% aqueous dimethylamine. The mixture was stirred in a sealed pressure bottle at 80° C. for 18 hours and then taken to dryness in vacuo. The gummy residue was mixed with water and dichloromethane. The aqueous layer was washed twice with dichloromethane. The organic solutions were combined, dried, filtered and evaporated, giving 6.23 g of 2-dimethylaminomethyl-1,4-bis(phenylmethyl)piperazine as a gum.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][C:7]=1[F:8].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Cl[C:40]1[N:45]=[C:44]([CH3:46])[N:43]=[C:42]([N:47]([CH2:57][C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=2)[CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[N:41]=1>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:8][C:7]1[C:2]([C:40]2[N:45]=[C:44]([CH3:46])[N:43]=[C:42]([N:47]([CH2:48][C:49]3[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=3)[CH2:57][C:58]3[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=3)[N:41]=2)=[CH:3][CH:4]=[C:5]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:6]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: Fc1nc(CN2CCOCC2)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(CN4CCOCC4)nc3F)n2)cc1
Temperature: 125 °C
Yield: 21 %

Procedure:
A mixture of 4-((5-bromo-6-fluoropyridin-2-yl)methyl)morpholine (277 mg, 1.007 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (49.3 mg, 0.060 mmol), bis(pinacolato)diboron (307 mg, 1.208 mmol) and potassium acetate (198 mg, 2.014 mmol) in 2 mL of dioxane was heated in a microwave at 125° C. for 20 min. Water (0.7 mL), KOAc (100 mg), 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (504 mg, 1.309 mmol) and Am-Phos (35 mg) were added and the mixture was heated in a microwave at 102° C. for 35 min. It was diluted with 5 mL of EtOAc and washed with 1 mL of 0.5 N NaOH. The EtOAc layer was concentrated and purified on a Redi-Sep pre-packed silica gel column (12 g) eluting with a gradient of 50-75% EtOAc in hexanes to give 4-(2-fluoro-6-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (115 mg, 21% yield) as a brown amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 8.60 (1H, dd, J=9.8, 1.8 Hz); 7.55 (1H, d, J=7.4 Hz); 7.24 (4H, d, J=8.2 Hz); 6.89 (4H, t, J=8.1 Hz); 4.76 (4H, d, J=7.4 Hz); 3.74 (3H, s); 3.72 (3H, s); 3.60 (6 H, m); 2.44 (7H, m). m/z (ESI, +ve ion) 545 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[CH:14][C:13](N=CN(C)C)=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)[OH:22]>O>[OH:22][C:13]1[CH:12]=[N:11][C:10]([C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=2)=[N:15][CH:14]=1
Reactant: CC(=O)c1cccc(-c2ncc(N=CN(C)C)cn2)c1
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1cccc(-c2ncc(O)cn2)c1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
5.10 g of N′-[2-(3-acetylphenyl)pyrimidin-5-yl]-N,N-dimethylformamidine (19 mmol) are suspended in 65 ml of water in a 250 ml one-necked flask provided with magnetic stirrer and condenser, 8.44 ml of 95-97% sulfuric acid (152 mmol) are added, and the mixture is stirred at a bath temperature of 130° C. for 2 h. The mixture is diluted with ice-water, during which a dark-brown resin deposits. The aqueous solution is decanted off and extracted with dichloromethane. The combined dichloromethane phases are dried, filtered and evaporated to dryness, and the residue is triturated with ether, filtered off with suction and dried (═K1). The deposited dark-brown resin is extracted by stirring with tetrahydrofuran, filtered off with suction, the crystals are discarded, and the mother liquor is evaporated to dryness (═R1). The aqueous phase from the dichloromethane extraction is evaporated to dryness, the residue is extracted by stirring 2× with tetrahydrofuran, and the combined decanted-off solutions are diluted with di-chloromethane, dried, filtered and evaporated to dryness (═R2). R1 and R2 are combined, adsorbed on silica gel and purified by chromatography (silica gel/dichloromethane+0-5% of methanol). The chromatography residue is triturated with ether, filtered off with suction, washed with ether and dried (═K2).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:29]=1)[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][C:10]([C:12](=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:11]2.[OH:30][C@@H:31]1[C@@H:35]([OH:36])[CH2:34][N:33]([C:37]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)=[O:38])[CH2:32]1>>[OH:36][C@@H:35]1[C@@H:31]([OH:30])[CH2:32][N:33]([C:37]([C:39]2[CH:40]=[CH:41][C:42]([C:2]3[CH:3]=[CH:4][C:5]4=[C:6]([CH:29]=3)[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:9][C:10]([C:12](=[O:20])[N:13]([CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH3:19])=[CH:11]4)=[CH:43][CH:44]=2)=[O:38])[CH2:34]1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CC1(C)OB(c2ccc(C(=O)N3C[C@H](O)[C@@H](O)C3)cc2)OC1(C)C
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4C[C@H](O)[C@@H](O)C4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by the procedure as described in Example 124 (Step F) using tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate and ((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone. MS APCI (+) m/z 591 (M+1) detected
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[C:13]1([C@@H:19]([NH2:22])[CH2:20][CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[C:13]1([C@@H:19]([NH:22][C:1]([CH2:2][C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[O:12])[CH2:20][CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: CC[C@H](N)c1ccccc1
Solvent: CC#N
Product: CC[C@H](NC(=O)Cc1ccccc1C(=O)O)c1ccccc1
Yield: 72 %

Procedure:
A mixture of homophthalic anhydride (810 mg, 5 mmol) and (S)-(−)-1-phenylpropylamine (676 mg, 5 mmol) in acetonitrile (15 ml) was heated under microwave irradiation at +150° C. for 15 min. White precipitate was collected by filtration, washed with heptane and dried in vacuo to give pure title compound in 72% yield (1.065 g). Alternatively, to a stirred solution of homophthalic anhydride (16.214 g, 0.1 mol) in acetonitrile (100 ml) (S)-(−)-1-phenylpropylamine (13.83 g, 0.102 mol) was added dropwise (exothermic reaction) and the obtained reaction mixture was refluxed for 5 min. It was allowed to cool and the product was isolated by filtration as above to give 23.4 g of colourless solid, 79% yield. LC-MS (m/z) 298.5 (MH+); tR=1.11. 1H NMR (500 MHz, DMSO-d6): 0.84 (t, J=7.3 Hz, 3H), 1.67 (quintet, J=7.3 Hz, 2H), 3.85 (d of AB system, J=15.1 Hz, 1H), 3.95 (d of AB system, J=15.1 Hz, 1H), 4.66 (q, J=7.6 Hz, 1H), 7.2 (unres. m, 1H), 7.25-7.34 (m, 5H), 7.45 (t, J=7.3 Hz, 1H), 7.8 (d, J=7.8 Hz, 1H), 8.39 (br. d, J=7.7 Hz, 1H, NH).