Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:3]=1.B(O)(O)[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[S:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>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.O.C(OCC)(=O)C.CC(N(C)C)=O>[S:27]1[CH:26]=[C:25]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:3]=2)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]1=2
Reactant: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(Cl)nc21
Reactant: OB(O)c1csc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(-c3csc4ccccc34)nc21
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-(2-(2-chloro-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol (950 g), thianaphthene-3-boronic acid (561 g), dichlorobis(triphenylphosphine)palladium(II) (10.1 g), potassium carbonate (791 g), water (3.25 L), and DMA (3.25 L) was stirred under a nitrogen atmosphere for 10 min. The stirred mixture was then heated at 70° C. for 14 h. Ethyl acetate (6.5 L) and water (3.25 L) were added, and the mixture was filtered through Celite (125 g) at 50° C., rinsing with ethyl acetate (1.0 L). The layers were separated, and the aqueous layer was extracted at 50° C. with additional ethyl acetate (7.5 L). The combined organic layers were washed with water (3×2.5 L), then distilled to remove about 2.5 L of solvent. Tetrahydrofuran (2.5 L) and silica bond thio silica gel (200 g) were added. The mixture was stirred at 70° C. for 16 hr, then was filtered, washing the pad with ethyl acetate (1.0 L). The combined filtrates were concentrated at atmospheric pressure to a volume of about 5 L, then the mixture was allowed to cool. The resulting solid was collected and washed with ethyl acetate (2×1.0 L) to provide the title compound.
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>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>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH:24]=[CH:23][CH:22]=1)[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1
Reactant: O=c1c(Br)coc2ccccc12
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(-c2coc3ccccc3c2=O)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
Prepared using a modified procedure of Hoshino et al. (Bulletin of the Chemical Society of Japan 1988, 61, (8), 3008-3010; herein incorporated by reference in its entirety). To a 10 mL round bottom flask was added 3-bromochromone (Gammill, R. B. Synthesis-Stuttgart 1979, (11), 901-903; herein incorporated by reference in its entirety) (225 mg, 1 mmol), K2CO3 (415 mg, 3 mmol), 3-methoxyphenylboronic acid (167 mg, 1.1 mmol), and PdCl2(PPh3)2(21 mg, 0.03 mmol). The flask was equipped with a reflux condenser and purged with N2, followed by addition of THF/H2O (2.5 mL/0.5 mL). The reaction was stirred at 80° C. for 4 hr. The reaction was then run through a plug of Celite and rinsed with EtOAc. The organic phase was washed with brine and dried over anhydrous Na2SO4. Purified by flash column chromatography (SiO2, 15% EtOAc/Hex) and recrystallized from CH2Cl2/Hex to afford 5 (128 mg, 51%) as an off-white solid. Analytical data for isoflavone 5: 1H NMR (500 MHz, CDCl3) δ 8.34 (d, J=9.5 Hz, 1H), 8.06 (s, 1H), 7.70 (app t, J=8.5 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.45 (app t, J =7.5 Hz, 1H), 7.37 (app t, J =8 Hz, 1H), 7.19 (s, 1H), 7.15 (d, J=7 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H), 3.87 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 176.4, 159.8, 156.4, 153.4, 133.9, 133.4, 129.8, 126.7, 125.5, 124.8, 121.5, 118.3, 114.7, 114.4, 55.6; LCMS: Mass calculated for C16H12O3, [M+H]+, 253. Found 253.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[C:15](C)[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2].[CH3:21]C1C=CC(C=O)=CC=1>>[C:1]([C:4]1[CH:20]=[CH:19][C:7]2[C:8](=[O:18])[C:9]3[CH:16]=[CH:15][C:14]([CH3:21])=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)([OH:3])=[O:2].[CH3:12][C:6]1[CH:5]=[C:4]([CH:20]=[CH:19][CH:7]=1)[CH:1]=[O:2]
Reactant: Cc1ccc2c(c1)C(=O)c1ccc(C(=O)O)cc1CC2
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc2c(c1)CCc1cc(C(=O)O)ccc1C2=O
Product: Cc1cccc(C=O)c1

Procedure:
20 G. of 2,5-bis(carbomethoxy)benzyltriphenylphosphonium bromide and 7.65 g. of m-methoxybenzaldehyde were added to 100 ml of acetonitrile and 22 ml of diazabicyclononene was added. After 16 hours the mixture was added to water and extracted with ethyl acetate. The extract was washed, dried and evaporated. The residue was refluxed for 1 hour in 250 ml of methanol and 250 ml of water containing 10 g. of potassium hydroxide. The solution was cooled and extracted with chloroform. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed, dried and evaporated to afford cis and trans 3'-methoxystilbene-2,5-dicarboxylic acid. 7.8 G. of this compound was hydrogenated for 11/2 hours in 800 ml of ethanol containing 1.5 g. of 5% palladium on carbon catalyst. The solution was filtered and evaporated to give 2-(m-methoxyphenethyl)-benzene-1,4-dicarboxylic acid which was cyclized according to the procedure set forth in Example I, A to afford 2-carboxy-8-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 220°-222° C. Similarly, other 8-substituted compounds of this invention may be obtained by reacting 2,5-bis(carbomethoxy) benzyltriphenylphosphonium bromide with a m-substituted benzaldehyde having a halogen such as fluoro, chloro or bromo, a lower alkyl of 1-4 carbons, or a lower alkoxy such as ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-pentyloxy, n-hexyloxy and the like. By reacting an o-substituted benzaldehyde or a p-substituted benzaldehyde with 2,5-bis(carbomethoxy) benzyltriphenylphosphonium bromide a 2-carboxy-9-substituted-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene or a 2-carboxy-7-substituted 10,11-dihydro-5-oxo-5 H-dibenzo[a,d]cycloheptene is obtained, respectively. For example 2-carboxy-7-methyl-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p of 235° C. was obtained from p-methylbenzaldehyde; 2-carboxy-8-methyl-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 196°-197° C. was obtained from m-methylbenzaldehyde; and 2-carboxy-9-methyl-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 232°-234° C. was obtained from o-methylbenzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[CH:15]1([NH2:18])[CH2:17]C1.CC1C2C(=O)OC(=O)[NH:29][C:24]=2[CH:23]=CC=1>>[CH:7]1([NH:6][C:4](=[O:5])[C:3]2[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:2]=2[NH:1][CH2:17][C:15]2[NH:18][CH2:23][CH2:24][N:29]=2)[CH2:8][CH2:9]1
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Reactant: NC1CC1
Reactant: Cc1cccc(N)c1C(=O)NC1CC1
Product: Cc1cccc(NCC2=NCCN2)c1C(=O)NC1CC1

Procedure:
2-Amino-N-cyclopropyl-6-methylbenzamide (prepared from cyclopropylamine and 5-methyl-2H-3,1-benzoxazine-2,4(1H)-dione using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give N-cyclopropyl-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-6-methylbenzamide.
Reaction SMILES: [OH:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18].[N:26]([CH2:29][C:30](OCC)=O)=C=O.[C:35]1([CH2:41]N2C(=O)CC(=O)NC2=O)[CH:40]=C[CH:38]=[CH:37][CH:36]=1.C(N(C(C)C)C(C)C)C>ClCCl>[C:29]([C:30]1[CH:40]=[C:35]([CH2:41][N:7]2[C:2]([OH:1])=[C:3]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[C:4](=[O:16])[N:5]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]2=[O:8])[CH:36]=[CH:37][CH:38]=1)#[N:26]
Reactant: CCOC(=O)CNC(=O)c1c(O)[nH]c(=O)n(Cc2ccccc2)c1=O
Reactant: CCOC(=O)CN=C=O
Reactant: O=C1CC(=O)N(Cc2ccccc2)C(=O)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cccc(Cn2c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc3ccccc3)c2=O)c1
Reaction time: 8 h
Yield: 73 %

Procedure:
Ethyl N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate. Ethyl isocyanatoacetate (2.24 mL, 20 mmoles) was added dropwise to a solution of 1-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (4.4 g, 20 mmoles) and ethyl diisopropylamine (6.9 mL, 40 mmoles) in dichloromethane (120 mL) and stirred overnight under argon. The mixture was washed with 1 molar hydrochloric acid, water and brine, dried and evaporated. The solid was slurried in diethyl ether, collected, washed with diethyl ether and hexane, dried to give the title compound (5.1 g, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.13 (br. s., 1 H), 9.84 (br. s., 1 H), 7.13-7.48 (m, 5 H), 4.95 (s, 2 H), 4.17 (d, 2 H), 4.15 (q, 2 H), 1.21 (t, J=7.20 Hz, 3 H)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:61])[C@@H:19]([NH:43][C:44](=[O:60])[O:45][CH2:46][CH:47]1[C:59]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:53]2[C:48]1=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:20]([CH3:42])([S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:21]>C(Cl)Cl>[CH3:42][C:20]([S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:21])[C@H:19]([NH:43][C:44](=[O:60])[O:45][CH2:46][CH:47]1[C:59]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:53]2[C:48]1=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:18](=[O:61])[NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[O:11]
Reactant: CC(C)(SC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(SC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCC=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a round bottom dry flask was added DCM (2 mL), and a 2 M solution of oxalyl chloride in DCM (0.100 mL, 0.200 mmol). The reaction was cooled to −78° C. Then slowly was DMSO (0.028 mL, 0.401 mmol) added over 5 min. The reaction was stirred at −78° C. for 30 min. Then (R)-(9H-fluoren-9-yl)methyl 1-(5-hydroxypentylamino)-3-methyl-1-oxo-3-(tritylthio)butan-2-ylcarbamate (100 mg, 0.143 mmol) in DCM (3 mL) was added to the reaction over 5 min and the reaction was stirred at −78° C. for 45 min. Then TEA (0.088 mL, 0.630 mmol) was added to the reaction and the reaction was stirred for additional 30 min at −35° C. The reaction was quenched with EtOAc (2 mL). The reaction was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (10 mL), water (10 mL) and saturated aqueous NaCl (10 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give (R)-(9H-fluoren-9-yl)methyl 3-methyl-1-oxo-1-(5-oxopentylamino)-3-(tritylthio)butan-2-ylcarbamate (95 mg, 0.14 mmol, 95% yield).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[S:11]C1C=CC=C2C=1CC(C)=C2.Br[C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][CH:26]([CH3:33])[C:27]2=[O:32].[Li]CCCC.S(Cl)Cl.C1C[O:45]CC1>Cl.CO>[CH3:33][CH:26]1[CH2:25][C:24]2[C:28](=[CH:29][CH:30]=[CH:31][C:23]=2[S:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][CH:2]([CH3:1])[C:10]3=[O:45])[C:27]1=[O:32]
Reactant: CC1Cc2c(Br)cccc2C1=O
Reactant: CC1=Cc2cccc(Sc3cccc4c3CC(C)=C4)c2C1
Reactant: C1CCOC1
Agent: Cl
Agent: ClSCl
Agent: [Li]CCCC
Solvent: CO
Product: CC1Cc2c(Sc3cccc4c3CC(C)C4=O)cccc2C1=O

Procedure:
Under an argon atmosphere, following the procedure described for bis(2-methyl-1H-inden-7-yl)sulfide, 22.9 g (85.2 mmol) of the above-described dioxalane-protected 4-bromo-2-methylindanone in 150 ml of THF, 34.1 ml of 2.5 M (85.3 mmol) nBuLi in hexanes, and 4.39 g (42.6 mmol) of SCl2 in 35 ml of hexanes gave crude dioxalane-protected 2-methyl-4-[(2-methyl-1-oxo-2,3-dihydro-1H-inden-4-yl)sulfanyl]-1-indanone, which was deprotected in a mixture of 150 ml of 16 M HCl and 150 ml of methanol for 7 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 35 mm, l 400 mm, eluant: CH2Cl2) and then recrystallized from hexanes. Yield, 3.53 g (26%) of a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)P(N(C)C)(N(C)C)=O.[OH-].[Na+]>[CH2:17]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:11][C:2]1=[O:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC(C(=O)O)c1cc(=O)[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C(=O)O)c1cc(=O)n(Cc2ccccc2)c2ccccc12
Yield: 39 %

Procedure:
α-(1,2-Dihydro-2-oxoquinol-4-yl)propionic acid (217 mg.) was dissolved in a mixture of hexamethylphosphoramide (2 ml.) and 2 N-sodium hydroxide (2 ml.). A solution of benzyl bromide (0.528 ml.) in hexamethylphosphoramide (2 ml.) was added dropwise to the stirred solution during 2 hours. The mixture was then poured into water (10 ml.), and the resulting mixture washed with chloroform (3×5 ml.). The aqueous solution was acidified to pH 1 with concentrated hydrochloric acid, and the resulting mixture was filtered and the white solid residue washed with water and dried in vacuo over phosphorus pentoxide. The solid was crystallised from ethanol to give α-(1-benzyl-1,2-dihydro-2-oxoquinol-4-yl)propionic acid, m.p. 178°-180° C. (decomposition), in 39% yield.
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.C1COCC1.Cl[C:38]([O:40][CH3:41])=[O:39]>N1C=CC=CC=1>[CH3:41][O:40][C:38](=[O:39])[NH:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1
Reactant: COC(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (30 mg, 71 μmol) was dissolved in a mixture of abs. THF (3 ml) and abs. pyridine (57.5 μl). At room temperature, pyridine (5×57 μl) and methyl chloroformate (5×33.6 mg, 5×356 μmol; 25 eq.) were added in a plurality of portions. The mixture was then heated at 80° C. for 12 h. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Kromasil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (31.1 mg, 91% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[NH2:31][C:32]1([C:35]([NH:37][S:38]([CH:41]2[CH2:43][CH2:42]2)(=[O:40])=[O:39])=[O:36])[CH2:34][CH2:33]1.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>CO.CN(C=O)C>[CH:41]1([S:38]([NH:37][C:35]([C:32]2([NH:31][C:24]([C:23]3[CH:22]=[C:21]([C:18]4[CH:19]=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=5[CH:17]=4)[CH:29]=[CH:28][CH:27]=3)=[O:25])[CH2:34][CH2:33]2)=[O:36])(=[O:40])=[O:39])[CH2:43][CH2:42]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: NC1(C(=O)NS(=O)(=O)C2CC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.9 %

Procedure:
In a 7 mL scintillation vial were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (30 mg, 0.077 mmol), 1-amino-N-(cyclopropylsulfonyl)cyclopropanecarboxamide hydrochloride (20 mg, 0.083 mmol), and HATU (40 mg, 0.10 mmol). DMF (0.4 mL) and DIPEA (0.1 mL, 0.57 mmol) were added, the vial was capped, and the solution was stirred at r.t. for 45 min. The reaction was diluted with MeOH, filtered, purified by prep HPLC, and the collected fractions were concentrated on a SPEEDVAC® to afford the title compound (23 mg, 52% yield) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.99 (br. s., 1H) 8.53 (q, J=4.78 Hz, 1H) 8.25 (br. s., 1H) 8.00 (dd, J=8.85, 5.49 Hz, 2H) 7.93 (s, 1H) 7.89 (t, J=7.78 Hz, 2H) 7.72-7.83 (m, 2H) 7.58 (t, J=7.48 Hz, 1H) 7.40 (t, J=8.85 Hz, 2H) 7.07 (br. s., 1H) 2.89-2.98 (m, 1H) 2.87 (d, J=4.58 Hz, 3H) 1.35-1.56 (m, 2H) 0.77-1.28 (m, 6H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.59 min, (ES+) m/z (MH+)=576. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: PHENOMENEX® Gemini C18, 4.6 mm, 3 μm, Rt=15.39 min, purity=100%; column: Waters XBridge phenyl 4.6×150 mm, 3.5 μm, Rt=14.50 min, purity=100%.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:18]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:15]
Reactant: OCCCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The above alcohol (1 g) was oxidised under Swern conditions (dimethyl sulphoxide (450 mg), oxalyl chloride (248 μl), triethylamine (1.58 ml)) in dichloromethane (25 ml) to give 7-(3,5-bistrifluoromethylbenzyloxy)heptan-1al. This was used directly in the next stage.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[O:8](C(OC(C)(C)C)=O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O>CN(C1C=CN=CC=1)C.C1COCC1>[C:12]([O:11][C:9]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7])=[O:8])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1ccc[nH]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.1 %

Procedure:
A mixture of pyrrole-2-carboxaldehyde (9.5 g, 0.1 mol), (BOC)2O (24.0 g, 0.11 mol) and DMAP (0.25 g) in THF (150 ml) was stirred at room temperature for 16 h. The solvent was removed under vacuum and the residue dissolved in CH2Cl2 (200 ml) and washed with 10% citric add, water and brine. The organic layer was dried (Na2SO4) and evaporated to give the desired product (20.9 g, 95%); δ (360 MHz, CDCl3) 1.65 (9H, s, 3 of CH3), 6.28-6.30 (1H, m, Ar--H), 7.18-7.19 (1H, m, Ar--H), 7.43-7.45 (1H, m, Ar--H). 2. trans-Methyl-2-N-tert-butyloxycarbonylpyrrol-2-yl)acrylate Prepared from the preceding aldehyde and methyl diethylphosphonoacetate as described for Intermediate 4 (step 3). The product (98%) was obtained as a pale yellow oil; δ (360 MHz, CDCl3) 1.63 (9H, s, 3 of CH3), 3.78 (3H, s, CH3), 6.21 (1H, d, J=16.0 Hz, vinyl CH), 6.21-6.22 (1H, m, Ar--H), 6.69-6.71 (1H, m, Ar--H), 7.38-7.39 (1H, m, Ar--H), 8.30 (1H, d, J=16.0 Hz, vinyl CH).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])=[C:4]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:3]=1.[C:32](Cl)(=[O:37])[CH2:33][C:34](Cl)=[O:35]>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[N:9]([CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[O:12])[C:32](=[O:37])[CH2:33][C:34](=[O:35])[N:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(N(C(=O)CNc2cc(F)c(F)cc2Nc2ccccc2)C(C)C)cc1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3cc(F)c(F)cc32)C(C)C)cc1
Reaction time: 16 h
Yield: 35.9 %

Procedure:
A solution of 5.62 g 2-(4,5-difluoro-2-phenylamino-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, (13.2 mmol) in 50 mL of tetrahydrofuran is transferred to an addition funnel. A solution of 1.60 mL of malonyl dichloride (16.53 mmol, 1.25 equiv) in 50 mL tetrahydrofuran is transferred to a separate addition funnel. Each solution of each reagent is simultaneously added dropwise over 20 min. to 250 mL of tetrahydrofuran at ambient temperature under nitrogen with vigorous agitation. After stirring 16 hrs. at ambient temperature, the reaction mixture is concentrated in vacuo. The residue is purified on flash grade silica gel using 40-50% ethyl acetate in hexane. The appropriate fractions were combined, evaporated in vacuo, dried under high vacuum for 2 hrs., and then triturated with hexane. The hexane is removed in vacuo and the residual solid is dried under high vacuum to provide 2.340 g of 2-(7,8-Difluoro-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as an off-white solid: 1H NMR (300 MHz, CDCl3) δ7.37 (m, 7H), 7.15 (m, 1H), 7.01 (m, 2H), 6.76 (dd, 1H, J=7.8, 11.1), 5.04 (m, 1H), 4.36 (d, 1H, J=16.3), 4.00 (d, 1H, J=16.5), 3.89 (s, 3H), 3.62 (d, 1H, J=12.2), 3.54 (d, 1H, J=12.2), 1.14 (m, 6H); low resolution MS (FAB)m/e 494 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.ClC(Cl)(O[C:26](=[O:32])OC(Cl)(Cl)Cl)Cl.[N:34]1([C:43]2[C:44]3[CH:51]=[CH:50][NH:49][C:45]=3[N:46]=[CH:47][N:48]=2)[C@H:42]2[C@H:37]([NH:38][CH2:39][CH2:40][CH2:41]2)[CH2:36][CH2:35]1>C(Cl)Cl>[N:46]1[C:45]2[NH:49][CH:50]=[CH:51][C:44]=2[C:43]([N:34]2[C@H:42]3[C@H:37]([N:38]([C:26]([NH:1][CH2:2][C:3]4[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=4)=[O:32])[CH2:39][CH2:40][CH2:41]3)[CH2:36][CH2:35]2)=[N:48][CH:47]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: c1nc(N2CC[C@H]3NCCC[C@H]32)c2cc[nH]c2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNC(=O)N2CCC[C@@H]3[C@H]2CCN3c2ncnc3[nH]ccc23)cc1
Reaction time: 3 h

Procedure:
To methyl 4-(aminomethyl)benzoate (25 mg, 0.12 mmol), was added DCM (376 μL), DIPEA (43 μL, 0.25 mmol) and triphosgene (11 mg, 0.037 mmol) at 0° C. The reaction was stirred for 2.5 hours before 4-[(3aR,7aR)-octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine (30.2 mg, 0.124 mmol) was added. The resulting solution was stirred for an additional 3 hours before being concentrated in vacuo and purified by mass triggered reverse phase HPLC. Lyophilization of the desired fractions gave the title compound (TFA salt) as a white solid. LRMS calc'd for C23H27N6O3 [M+H]+, 435; found 435. Jak1 activity: ++.