Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:18]([Si:22]([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)Cl)([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[Si:22]([O:8][CH:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC1CC=CCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OC=C1C=CCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-cyclohexene-1-methanol (Aldrich, 13.0 mL, 0.11 mol), N,N-diisopropylethylamine (43 mL, 0.244 mol) and 4-dimeehylaminopyridine (2.70 g., 0.022 mol) in 375 mL of dry CH2Cl2 under N2 at 25° C. was added tert- butyldiphenylchlorosilane (32 mL, 0.123 mol). The mixture was stirred at 25° C. for 48 hours. The reaction mixture was washed sequentially with 150 mL portions of 1N HCl, water, brine and dried over anhydrous MgSO4. The solvent was evaporated. The residue was loaded onto a 4"×4" column of silica and slowly eluted using hexanes as eluant. 3-(tert-butyldiphenylsilyloxymethylene)-1-cyclohexene, 33.6 g (86%), was obtained as a colorless oil which was homogenous by TLC (Rf=0.4, hexanes).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22].[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34](O)=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34]([NH:22][C@H:21]([C:20]([NH:19][C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@@H:4]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:24])[CH3:23])=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: C[C@H](N)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a stirred solution of N1-[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-L-alaninamide (6g) (765 mg, 2.351 mmol) in dichloromethane (10 mL) was added 3,5-difluorophenylacetic acid (450 mg, 2.614 mmol), HOBt (441 mg, 3.265 mmol), NMM (330 mg, 3.267 mmol) and EDAC-HCl (626 mg, 3.265 mmol). The mixture was stirred at ambient temperature under nitrogen overnight. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated and then washed in succession with 1N aqueous HCl and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 2:1 (v/v) ethyl acetate:hexanes to afford the title compound (968 mg, 86%) as a white solid. TLC Rf=0.30 (2:1 ethyl acetate:hexanes). 1H NMR (300 MHz, DMSO-d6) δ1.11 (d, 3H, J=7.0 Hz), 3.46 (q AB, 2H, J=14.4 Hz), 4.24 (m, 1H), 4.95 (m, 1H), 5.61 (d, 1H, J=6.6 Hz), 6.94 (m, 2H), 7.02-7.29 (m, 5H), 7.32-7.40, (m, 6H), 8.32 (m, 1H), 10.29 (br, 1H). MS APCI, m/z=480 (M+1). LC/MS: 2.31 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[F:23])[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:45]=[CH:46][CH:47]=2)O1.C1(C)C=CC=CC=1.C(O)C.O.C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:42]4[CH:43]=[C:44]([NH:48][S:49]([CH3:52])(=[O:50])=[O:51])[CH:45]=[CH:46][CH:47]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4F)c3)c3cc(Br)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4F)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Temperature: 80 °C
Yield: 124.7 %

Procedure:
5-Bromo-3-(1-(2-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (140 mg, 0.267 mmol) and N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methane sulfonamide (Intermediate 3) (95 mg, 0.32 mmol) were added to a solution of toluene/ethanol/water (5/5/2.5 ml) previously purged with argon (10 min). The reaction mixture was purged with argon for a further 15 mins, followed by the addition of potassium carbonate (74 mg, 0.534 mmol) and Pd(PPh3)4 (15 mg, 0.0133 mmol). The resulting mixture was heated to reflux at 80° C. for 2 h. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was cooled and diluted with ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 205 mg of crude product which was taken as such for next reaction. MS: m/z=616.1 (M+1).
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:35](/[CH3:40])=[C:36](/[F:39])\[CH:37]=O)[C:20]=1[O:41][CH2:42][CH3:43]>>[Br:18][C:19]1[C:28]2[C:27]([CH3:29])([CH3:30])[CH2:26][CH:25]=[C:24]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:23]=2[CH:22]=[C:21](/[C:35](/[CH3:40])=[C:36](/[F:39])\[CH:37]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:20]=1[O:41][CH2:42][CH3:43]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: CCOc1c(/C(C)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)(C)C
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)(C)C

Procedure:
Following General Procedure I-1, ethyl 4(diethoxyphosphoryl)-3-methyl-but-2E-enoate (92-mg, 0.35 mmol) and (2E)-3-(4-bromo-8-tert-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-enal (Compound A-152, 37 mg, 0.09 mmol) were reacted to give the title compound as a colorless oil after purification by column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C@H:4]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)[C:5]([OH:7])=O.[CH2:19]([CH2:21][NH2:22])[OH:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:20][CH2:19][CH2:21][NH:22][C:5]([C@@H:4]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)[CH2:3][CH:2]([CH3:1])[CH3:18])=[O:7]
Reactant: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)O)c1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)NCCO)c1
Reaction time: 2 h
Yield: 29.9 %

Procedure:
(S)-4-Methyl-2-(3-methyl-benzoylamino)-pentanoic acid (1 g. 4.0 mmol), ethanolamine (270 mg, 4.4 mmol) and HOBt (596 mg, 4.4 mmol) were treated with DCM (20 mL) followed by EDCI (845 mg, 4.4 mmol). The reaction was allowed to stir for 2 h and then purified directly by silica gel column chromatography using ethyl acetate and hexane to afford the product (350 mg, 30%) as a solid: 1H NMR (CDCl3, 400 MHz) δ 0.89-0.99 (m, 6H), 1.67-1.79 (m, 3H), 2.37 (s, 3H), 3.31-3.41 (m, 1H), 3.42-3.52 (m, 1H), 3.61 (dd, 1H, J1=2.7, J2=8.1), 7.24-7.34 (m, 2H), 7.43 (dd, 1H, J1=J2=5.3), 7.57-7.63 (m, 2H); HPLC-MS calcd. for C16H24N2O3 (M+H+) 292.18, found 292.2.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.O.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:5]([C:6]1[CH:14]=[CH:13][C:9]([C:10](=[O:11])[C:6]2[CH:14]=[CH:13][CH:9]=[CH:8][CH:7]=2)=[CH:8][CH:7]=1)(=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(c1ccccc1)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
To a stirred slurry of 56 g of aluminum chloride in 150 ml of benzene under reflux was added dropwise 40 g of terephthaloyl chloride dissolved in 250 ml of benzene. When the addition was complete the reaction was refluxed for 15 minutes, cooled, and 250 ml of water was added slowly. The benzene layer was separated and the aqueous layer was extracted with methylene chloride (2×300 ml). The combined organic layers were washed with 1 M NaOH solution (2×400 ml) and water (400 ml), dried (MgSO4), filtered, and the solvents were removed under reduced pressure to a nearly colorless solid. Recrystallization from 95% ethanol gave 46.8 g of colorless 1,4-dibenzoylbenzene, m.p. 160°-162°. Reduction of 20 g of this material with 1.8 g of sodium borohydride in 250 ml of ethanol gave 14.2 g of colorless 1,4-dibenzylolbenzene m.p. 142°-145°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[NH:11][C:10](=O)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([CH3:14])[N:11]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2ccc(Cl)cc2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-6-methyl-1H-pyrimidin-2-one (11.0 g, 50.0 mmol) and phosphoryl chloride (20 mL) according to step 3 of the general procedure I. Obtained as an off-white solid (6.8 g, 57%). MS (ISP) 239.0 [(M+H)+]; mp 116-117° C.
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[NH2:16][CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-]>CN(C)C(=O)C>[C:18]1([CH2:17][NH:16][CH2:3][C:4]2[N:5]=[C:6]3[C:11](=[N:12][CH:13]=2)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]3[NH2:15])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: NCc1cccc2ccccc12
Agent: Br
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(CNCc3cccc4ccccc34)cnc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (51 mg, 0.2 mmol) in anhydrous N,N dimethylacetamide was added 1-aminomethyl-naphthalene (31.67 ul, 0.22 mmol). The reaction mixture was stirred at 50° C. overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 9 mg product was obtained. Yield: 15%; 1H NMR(500 MHz, DMSO-d6): δ 4.6479(s, 2H ), 4.7893(s, 2H), 7.575–7.6244(m, 3H), 7.74232–7.7570(d, J=6.91 Hz, 1H), 7.9935–8.0276(dd, J1=8.06 Hz, J2 =8.995 Hz, 2H), 8.1670–8.1831(d, J=8.04 Hz, 1H), 8.8430(s, 1H); ESI-MS: m/z 332 (M++1)
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][S:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:7]=1)C.Br>C(O)(=O)C>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:31])=[O:3])=[CH:7][C:8]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[CH2:24][S:25][CH2:26][C:27]([F:30])([F:28])[F:29]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(O)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1

Procedure:
{4-Methoxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester (1.5 g, 3.6 mmol) was treated with 48% hydrogen bromide in acetic acid (1:1; 20 mL) at 100° C. overnight. After work-up with EtOAc and H2O, the crude material was purified by preparative HPLC to give {4-hydroxy-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1I.[C:11]([C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)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>[NH2:19][C:16]1[N:17]=[CH:18][C:13]([C:11]#[C:12][C:3]2[C:4]([NH2:9])=[N:5][C:6]([NH2:8])=[N:7][C:2]=2[Cl:1])=[CH:14][CH:15]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: Nc1nc(N)c(I)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(C#Cc2c(N)nc(N)nc2Cl)cn1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 850 mg (3.1 mmol) 6-chloro-5-iodo-pyrimidine-2,4-diamine, 2.2 g (19 mmol) 5-ethynyl-2-amino-pyridine, 59 mg (0.31 mmol) CuI, 218 mg (0.31 mmol) PdCl2(PPh3)2 and 21 mL triethylamine in 25 mL dry DMF. Yield after purification by RP-HPLC: 720 mg (88%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:11]([O:15][C:16](=[O:31])[NH:17][C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19](=[O:26])[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:14])([CH3:13])[CH3:12].C(O)(C)C>CCOC(C)=O>[C:11]([O:15][C:16](=[O:31])[NH:17][C@@H:18]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:19]([N:20]1[CH2:21][CH2:22][N:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:24][CH2:25]1)=[O:26])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCNCC1
Reactant: Fc1ccc2nccn2n1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc3nccn3n2)CC1
Yield: 78 %

Procedure:
To 305 mg (2.23 mmol) of 6-fluoroimidazo[1,2-b]pyridazine, was added 1.00 g (3.34 mmol) of (S)-tert-butyl(4-methyl-1-oxo-1-(piperazin-1-yl)pentan-2-yl)carbamate, 10 mL of isopropyl alcohol, and 0.93 mL (6.68 mmol) of TEA. This was microwaved at 150° C. for 0.5 hr. It was diluted with EtOAc, washed with brine, and the organic layer was dried over MgSO4, and then concentrated. It was purified on the ISCO with a 40 gram column eluting with 0-10% MeOH/DCM to obtain the desired product in 78% yield.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>O1CCCC1>[C:33]([O:24][CH2:23][C:22]1[C:17]([N:10]2[N:9]=[CH:8][C:7]3[C:12](=[C:13]([F:15])[CH:14]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[C:11]2=[O:16])=[N:18][CH:19]=[CH:20][C:21]=1[Cl:25])(=[O:35])[CH3:34]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3CO)ncc2c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCc1c(Cl)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-tert-butyl-2-(4-chloro-3-(hydroxymethyl)pyridin-2-yl)-8-fluorophthalazin-1(2H)-one 104a (150 mg, 0.42 mmol) and triethylamine, Et3N (0.12 mL, 0.84 mmol) in tetrahydrofuran, THF (2.5 mL) was added acetyl chloride, AcCl (44 μl, 0.62 mmol). The mixture was stirred at rt for 1 h and quenched with water, extracted with ethylacetate, EA. The combined organic layers were dried over Na2SO4, filtered and concentrated to give 104b (160 mg) as a colorless oil. MS-ESI: [M+H]+ 404.1
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10](CC=C)[C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][C:22]#[N:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].C1([SiH3])C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:18])[N:7]([CH2:19][CH2:20][CH2:21][C:22]#[N:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCC#N)c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Product: CCCCn1c(=O)n(CCCC#N)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.1 %

Procedure:
4-[3-Butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butanenitrile (2.1 g, 6 mmol) was stirred in a mixture of nitrogen degassed DCM (20 ml) and AcOH (2 ml). Tetrakis(triphenylphosphine)palladium (675 mg, 0.6 mmol) and phenyl silane (7.4 ml, 60 mmol) were added and the mixture stirred at rt for 2 d. This was then evaporated and the residue triturated with a mixture of diethylether:cyclohexane (1:1) to afford the title compound (1.47 g, 60%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCO2
Agent: Br
Solvent: CC(=O)O
Product: O=C1CCOc2ccc(O)cc21
Yield: 14.3 %

Procedure:
A mixture of 36 g of 6-methoxychroman-4-one and 290 ml of 48% hydrogen bromide solution in 290 ml of glacial acetic acid was heated to reflux for 3 hours. The solvent was removed in vacuo and the residue diluted with 2 l of water and stored in a refrigerator overnight. The resulting solid was filtered, washed with water and dried, 25.7 g. The original filtrate was extracted with ethyl acetate and the organic layer dried over sodium sulfate and concentrated to give an additional 4.75 g of the titled product.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]3[NH:17][C:16]4[C@@H:18]([CH3:22])[NH:19][C:20](=[O:21])[C:15]=4[CH:14]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[OH:44][C:38]([C:40]([F:43])([F:42])[F:41])=[O:39].[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][C@H:24]([NH:23][C:3]2[N:2]([CH3:1])[C:11](=[O:12])[C:10]3[C:5](=[C:6]([C:13]4[NH:17][C:16]5[C@@H:18]([CH3:22])[NH:19][C:20](=[O:21])[C:15]=5[CH:14]=4)[CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH2:25]1
Reactant: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(N[C@@H]5CCC[C@H](NC(=O)OC(C)(C)C)C5)nc34)[nH]c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(N[C@H]5CCC[C@@H](N)C5)nc34)[nH]c21
Yield: 98.9 %

Procedure:
A solution of (rac)-tert-butyl ((cis)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (509, see below) (47 mg, 0.093 mmol) and TFA (71.5 pt, 0.928 mmol) in DCM (928 pt) was stirred at RT for 1.5 h when mostly product was observed via LCMS. The reaction mixture was concentrated to give (rac)-2-(((cis)-3-aminocyclohexyl)amino)-3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one TFA salt (506, 48 mg, 0.092 mmol, 99% yield) as an off-white solid and a 2.6:1 ratio of diastereomers via LCMS and 1.3:1 via 1H NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.33 (m, 1H) 1.33-1.46 (m, 5H) 1.46-1.56 (m, 1H) 1.89 (d, J=12.72 Hz, 1H) 1.98 (d, J=11.74 Hz, 1H) 2.06 (d, J=10.56 Hz, 1H) 2.30-2.39 (m, 1H) 3.05-3.17 (m, 1H) 3.45 (s, 3H) 4.01-4.15 (m, 1H) 4.50-4.61 (m, 1H) 6.93-7.01 (m, 1H) 7.06 (d, J=4.11 Hz, 1H) 7.17 (t, J=7.63 Hz, 1H) 7.62 (s, 0.42H) 7.66 (s, 0.58; H) 7.84 (d, J=7.63 Hz, 1H) 7.88-8.00 (m, 3H) 11.78 (s, 0.42; H) 11.91 (s, 0.58; H). 19F NMR (376 MHz, DMSO-d6) δ ppm −73.81 (s, 3F). MS (ESI, pos. ion) m/z: 407.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:15](O)[CH2:16][OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1([O:17][CH2:16][CH2:15][O:13]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)CCC(=O)c1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)CCC1(c2ccccc2)OCCO1

Procedure:
To a solution of 2.0 g of 3-benzoylpropionic acid methyl ester in 50 ml of dry benzene were added 0.7 ml of ethylene glycol and 0.01 g of anhydrous-p-toluene-sulfonic acid and the mixture was heated under reflux for 17 hours while removing water formed during the reaction by using a molecular sieve. After cooling, the reaction mixture was washed with a saturated sodium chloride aqueous solution, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 1.8 g of 4,4-ethylenedioxy-4-phenylbutyric acid methyl ester.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].[CH2:19]([NH:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21]>C1COCC1.C(Cl)(Cl)Cl>[CH2:19]([N:22]([CH2:23][CH2:24][CH3:25])[C:13](=[O:15])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[C:7]([N+:16]([O-:18])=[O:17])[CH:8]=1)[CH2:20][CH3:21]
Reactant: CCCNCCC
Reactant: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Yield: 74.4 %

Procedure:
Thionyl chloride (50 ml, 680 mmol) was added dropwise to a solution of (4-hydroxy-3-nitrophenyl)acetic acid (25 g, 127 mmol) obtained in 1) in THF (100 ml) at room temperature, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated, and the resultant residues were dissolved in chloroform (250 ml) and added dropwise over 1 hour to a solution of dipropylamine (35 ml, 255 mmol) in chloroform (300 ml) under cooling with ice-bath. After this addition, the reaction solution was washed with water and aqueous saturated sodium bicarbonate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residues were crystallized from ethyl acetate-hexane, whereby N,N-dipropyl-(4-hydroxy-3-nitrophenyl) acetamide (26.5 g) was obtained as crystals with a mp of 55 to 57° C.
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.Cl.O1CCOC[CH2:13]1>CO>[OH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:13])=[O:9])=[N:6][CH:7]=1
Reactant: C1COCCO1
Reactant: O=C(O)c1cnc(O)cn1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cnc(O)cn1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
Commercially available 5-hydroxypyrazine-2-carboxylic acid (1.00 g, 7.14 mmol) was dissolved in methanol (5 mL), and a 4N hydrochloric acid/dioxane solution (25 mL) was added, followed by stirring at 60° C. for 1.5 hours and heating to reflux at 80° C. for 2.5 hours. The reaction solution was brought back to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate (20 mL) was added to the resulting residue to allow it to be suspended. The resulting precipitate was filtered off, and washed with ethyl acetate, followed by vacuum drying, to afford the desired compound (673 mg, yield 61%) as an orange-brown solid.