Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[C:14](B(O)O)[C:15]([F:18])=[N:16][CH:17]=1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=1.C([O-])(=O)C.[K+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[C:14]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=2)[C:15]([F:18])=[N:16][CH:17]=1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1nc(N)nc(Cl)n1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)c1cnc(F)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(N)nc(-c2cc(C(C)CO[Si](C)(C)C(C)(C)C)cnc2F)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
A yellow solution of 5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-fluoropyridin-3-ylboronic acid (1.79 g, 5.71 mmol), 4-chloro-6-methyl-1,3,5-triazin-2-amine (Example 9; 0.826 g, 5.71 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich, St. Louis, Mo.; 0.202 g, 0.286 mmol), and potassium acetate (1.682 g, 17.14 mmol) in a mixture of dioxane (50 mL) and water (12.50 mL) was stirred under argon at 100° C. for 2 h. The yellow reaction mixture was subsequently partitioned between CH2Cl2 (200 mL) and half-saturated brine (100 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated onto silica gel. Chromatographic purification (silica gel, 0 to 70% EtOAc/hexanes) provided 4-(5-(1-(tert-butyldimethylsilyloxy)propan-2-yl)-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (1.11 g, 2.94 mmol, 51.5% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=9.3, 2.4 Hz, 1H), 8.19 (d, J=1.4 Hz, 1H), 5.49 (br. s., 2H), 3.63-3.76 (m, 2H), 2.96-3.07 (m, 1H), 2.55 (s, 3H), 1.34 (d, J=7.0 Hz, 3H), 0.85 (s, 9H), −0.02 (s, 3H), −0.03 (s, 3H). 19F NMR (377 MHz, CDCl3) δ −68.99 (d, J=6.0 Hz, 1F). m/z (ESI, +ve) 378.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]#[N:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].C(Cl)(Cl)Cl.[OH2:21]>>[CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([NH2:14])=[O:21])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(OC)nc2nc(C#N)cn2c1C
Reactant: O
Solvent: ClC(Cl)Cl
Product: CCc1c(OC)nc2nc(C(N)=O)cn2c1C
Yield: 97 %

Procedure:
A suspension of 10.0 g of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carbonitrile of Step A and 20.0 g of Amberlite IRA-400 (base form) in 200 ml of water was stirred rapidly at reflux and after 41/2 hours, the mixture was cooled. Chloroform was added to dissolve the precipitated product and the two phase mixture was filtered to remove the Amberlite. The layers were separated and the aqueous phase was extracted with chloroform. The combined chloroform layers were dried over MgSO4, filtered and evaporated to dryness. The solid product was crystallized from methanol to obtain 10.5 g (97% yield) of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxamide as white needles melting at 256°-259° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:20])[NH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:9]=1)([O-])=O.[OH-].[Na+].[H][H].Cl>C(O)C.O.[Pd]>[NH2:1][C:4]1[C:5](=[O:20])[NH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:9]=1
Reactant: CCCOc1ccccc1-c1ccc([N+](=O)[O-])c(=O)[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1-c1ccc(N)c(=O)[nH]1

Procedure:
A solution of 3-nitro-6-(2-propoxyphenyl)-2(1H)-pyridinone (0.3 g) in a mixture of ethanol (20 ml) and water (10 ml) containing 2 Normal sodium hydroxide (0.75 ml) was shaken with 10% palladium on charcoal (0.05 g) under hydrogen at atmospheric pressure until the uptake of hydrogen had ceased. The filtered solution was treated with dilute hydrochloric acid to pH 6 and evaporated to half its volume. Water (5 ml) was added and the mixture was filtered to give a crude product, 0.29 g, m.p. 158°-161° C. Recrystallization from 50% aqueous ethanol afforded the pure title compound, 0.11 g, m.p. 164.5°-165.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([Cl:25])=[C:7]([C:21]([Cl:24])=[CH:22][CH:23]=1)[CH2:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH3:20])[CH:16]=[CH:15]2.N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl>[C:32]([NH:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([Cl:25])=[C:7]([C:21]([Cl:24])=[CH:22][CH:23]=1)[CH2:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH3:20])[CH:16]=[CH:15]2)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(OCCN)c3Cl)c2n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCCOc1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a solution of 8-[3-(2-aminoethoxy)-2,6-dichlorobenzyloxy]-2-methylquinoline (11 mg) in dichloromethane were added pyridine (3.46 g) and acetic anhydride (4.47 mg), and the mixture was stirred for 30 minutes. The reaction mixture concentrated, and the reside was purified by preparative thin-layer chromatography (dichloromethane:methanol=10:1, V/V) to give 8-[3-(2-acetamidoethoxy)-2,6-dichlorobenzyloxy]-2-methylquinoline (6 mg) as an amorphous powder.
Reaction SMILES: [O:1]([C@@H:9]1[C@@H:16]2[N:12](/[C:13](=[N:17]/[C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])/[O:14][CH2:15]2)[CH2:11][CH2:10]1)[Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[OH:1][C@@H:9]1[C@@H:16]2[N:12](/[C:13](=[N:17]/[C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])/[O:14][CH2:15]2)[CH2:11][CH2:10]1
Reactant: Cc1c(/N=C2\OC[C@@H]3[C@@H](O[Si](C)(C)C(C)(C)C)CCN23)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(/N=C2\OC[C@@H]3[C@@H](O)CCN23)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of compound 2D (11.0 mg, 0.0250 mmol) in THF (1 mL) at 0° C. was added a 1.0 M TBAF solution in THF (0.250 mL, 0.250 mmol). After stirring at rt for 1 h, saturated aqueous NH4Cl and EtOAc were added. The layers were separated, and the organic layer was washed with brine, then dried over MgSO4, filtered and concentrated. Purification via flash chromatography (silica gel, 0-85% EtOAc in hexane) provided the title compound (4.6 mg). LCMS: m/z 292 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C@H:15]1[CH2:22][N:21]2[C:23]3[CH:24]=[C:25]([C:36]([O:38][CH3:39])=[O:37])[CH:26]=[CH:27][C:28]=3[C:29]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:20]2[C:19]2[CH:40]=[CH:41][CH:42]=[CH:43][C:18]=2[O:17][CH2:16]1)C1C=CC=CC=1.CC(O)=O>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH:30]1([C:29]2[C:28]3[CH:27]=[CH:26][C:25]([C:36]([O:38][CH3:39])=[O:37])=[CH:24][C:23]=3[N:21]3[C:20]=2[C:19]2[CH:40]=[CH:41][CH:42]=[CH:43][C:18]=2[O:17][CH2:16][C@@H:15]([O:14][CH2:13][CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH2:22]3)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCC1CCCN1Cc1ccccc1)COc1ccccc1-3
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCC1CCCN1)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
To a solution of methyl (7S)-7-[(1-benzylpyrrolidin-2-yl)methoxy]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.07 M) in EtOAc, was added an excess of AcOH (>50 eq) and Pd(OH)2/C. The atmosphere in the reaction flask was charged with H2 and the reaction stirred vigorously under a H2 atmosphere (balloon) at RT for 2 d. The mixture was filtered and the filtrate concentrated in vacuo. The crude was purified by FC (gradient from EtOAc/PE 6:4+1% NEt3 to EtOAc/PE 8:2+1% NEt3+5% MeOH) to afford the product (50%). (ES+) m/z 489 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[CH2:10][C:9]2([CH3:24])[CH3:23])=[O:5])[CH3:2].[C:25]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:32]3[CH:33]=[CH:34][C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:30][CH:31]=3)[CH:19]=[CH:20][CH:21]=1)[CH2:10][C:9]2([CH3:24])[CH3:23])=[O:5])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(-c3ccc(C(C)(C)C)cc3)c1)N2
Temperature: 120 °C
Yield: 31.4 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.0 g, 2.6 mmol), 4-tert-butylbenzeneboronic acid (0.50 g, 2.6 mmol), bis(triphenylphosphine)palladium (II) chloride (180 mg, 0.26 mmol) and 2 M sodium carbonate (3.9 mL, 7.8 mmol) in dioxane (5 mL) was heated for 3 h at 120° C. After coiling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-(4′-tert-butyl-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.36 g, 31%) as a white solid: MS (ESI) M+1=442.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl[C:40]1[CH:45]=[N:44][CH:43]=[CH:42][N:41]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:25]=[CH:26][C:27]([C:40]3[CH:45]=[N:44][CH:43]=[CH:42][N:41]=3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: Clc1cnccn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3cnccn3)cc2)n1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyrazin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one is prepared from 5-(4-chloro-phenyl)-1-phenyl-6-[4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one and 2-chloro-pyrazine by using the method described in example 338 except that the reaction mixture is stirred at 100° C. for 14 hours: 1H NMR (CDCl3) δ (ppm) 9.02(d, 1H), 8.67(t, 1H), 8.55(d, 1H), 8.35(s, 1H), 8.15 (d, 2H), 7.95(d, 2H), 7.51(m, 4H), 7.37 (t, 1H), 7.33(d, 2H), 7.14(d, 2H). HPLC-MS calculated C27H17ClN6O (M+1+): 477.1. Found: 477.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[NH:14][CH:15]=[CH:16][CH:17]=3)=[CH:12][C:3]1=2.[C:19](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:1][C:2]1([CH3:18])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[N:14]([CH3:19])[CH:15]=[CH:16][CH:17]=3)=[CH:12][C:3]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc[nH]3)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a mixture of 4,4-dimethyl-6-(1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one (1.5 g, 6.2 mmol) in dimethylformamide (20 mL) at room temperature was added sequentially potassium carbonate (4.28 g, 31 mmol) and a solution of methyl iodide (1.16 mL, 19 mmol) in dimethylformamide (5 mL). After 1 h, the reaction mixture was boiled. The reaction was cooled to room temperature, poured into water (50 mL) and extracted with ethyl ether (2×50 mL). The organic layers were combined, washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (40% ethyl acetate/hexane) gave the title compound as an off-white powder (0.5 g, 31%) mp 230° C. 1H NMR (CDCl3) δ1.71 (s, 6H), 3.42 (s, 3H), 6.31 (dd, 1H, J=2.9, 5.9 Hz), 6.47 (m, 1H), 6.88 (m, 1H), 6.94 (d, 1H, J=8.6 Hz), 7.26 (d, 1H, J=2.2 Hz), 7.41 (dd, 1H, J=2.2, 8.6 Hz), 8.43 (bs, 1H). MS ((−) ESI) m/z 255 [M−H]−. Anal. Calcd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C, 68.59; H, 6.16; N, 10.49.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].C(N(CC)CC)C.[N:14]([C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1)=[C:15]=[O:16]>ClCCCl>[CH3:5][C:2]1([CH3:6])[C:3](=[NH:4])[N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:18]=2)[C:15](=[O:16])[NH:1]1
Reactant: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Reactant: CC(C)(N)C#N
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=N
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 47.3 %

Procedure:
To a solution of compound 9 (641 mg, 7.62 mmol) and triethylamine (168 mg, 1.66 mmol) in 1,2 dichloroethane (8.4 mL) at 0° C. under argon was dropwise added a solution of the isocyanate 8a (1.54 g, 7.28 mmol) in 1,2 dichloroethane (3.5 mL). The solution was stirred at 0° C. for 35 min and the ice bath was then removed and stirred at room temperature for an additional 30 min. The solution was then evaporated to dryness and purified by flash chromatography using EtOAc/Hexane (6:4) as an eluant to give pure compound 10a (1.02 g, 47%). 1H NMR (300 MHz, Acetone-d6) δ: 1.54 (m, 6H), 7.45 (broad s, 1H), 8.12 (d, 1H, J=8.46 Hz), 8.29 (dd, 1H, J1=6.90 Hz, J2=1.61 Hz), 8.46 (s, 1H), 8.51 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:26])[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]CC4C=CC=CC=4)=[C:13]([F:25])[CH:12]=3)[C:9]=2[CH:10]=1>C(O)C.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([OH:26])[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[C:9]=2[CH:10]=1
Reactant: Oc1cc(F)cc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccc(-n2ncc3c(O)cc(F)cc32)cc1F
Yield: 91.1 %

Procedure:
A solution of 6-fluoro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazol-4-ol (D8) (470 mg, 1.34 mmol) in ethanol (20 mL) and ethyl acetate (20 mL) was hydrogenated in an H-cube over a 10% palladium on charcoal catalyst. The resulting solution was concentrated to yield the title compound (E4) (320 mg).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:24]2[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=2)[N:5]2[C:10]3[CH:11]=[CH:12][N:13]([S:14]([C:17]4[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[C:9]=3[N:8]=[CH:7][C:6]=12.[OH2:31]>O1CCOCC1>[Br:1][C:2]1[N:3]=[C:4]([C:24]2[C:25]([CH:30]=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=2)[N:5]2[C:10]3[CH:11]=[CH:12][N:13]([S:14]([C:17]4[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=4)(=[O:16])=[O:15])[C:9]=3[N:8]=[CH:7][C:6]=12
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(-c4cccnc4C)n23)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(-c4cccnc4C=O)n23)cc1
Temperature: 105 °C
Yield: 69 %

Procedure:
The 3-bromo-1-(2-methylpyridin-3-yl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.500 g, 1.03 mmol, prepared using J.1 from Example #2, Step B with 2-methylnicotinic acid, L.2 with POCl3 and AB) in 1,4-dioxane (20 mL) was treated with SeO2 (0.210 g, 1.89 mmol) then the mixture was heated at about 105° C. for about 1 h. The mixture was cooled to rt then water (0.6 mL) was added. The mixture was heated to reflux for about 3 days. The mixture was cooled to rt then concentrated in vacuo. The material was purified using a 10 g silica column eluting with EtOAc. The impure fractions were combined and concentrated then the material was purified using a 10 g silica column eluting with EtOAc. The materials were combined to give 3-(3-bromo-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)picolinaldehyde (0.355 g, 69%): LC/MS (Table 2, Method b) Rt=3.53 min; MS m/z 480 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1)=O)(C)(C)C.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[NH2:8][C:9]([CH3:26])([CH3:27])[CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:16][CH:17]=1
Reactant: CC1CC(=O)NN=C1c1ccc(NCC(C)(C)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1CC(=O)NN=C1c1ccc(NCC(C)(C)N)cc1
Reaction time: 2 h
Yield: 75.2 %

Procedure:
The 6-[4-(2-t-butoxycarbonylamino-2-methylpropylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (3.74 g) obtained in (1-c) above was dissolved in ethyl acetate (10 ml), and 15% hydrogen chloride-ethyl acetate solution (40 ml) was added. The mixture was stirred for 2 hours, and the solvent was evaporated under reduced pressure. The residue was dissolved in water, made alkaline with sodium carbonate, and extracted with chloroform. The extract was dried over MgSO4, and the solvent was evaporated to give 6-[4-(2-amino-2-methylpropylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (2.06 g).
Reaction SMILES: [Mg].CN(CCN(C)C)C.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18].Br[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: BrC1CCCC1
Agent: CN(C)CCN(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a 30 L jacketed reactor, dry THF (6 L) and magnesium turnings (243.0 g, 10 mol, 1.5 eq.) were added under N2. In a separate flask, FeCl3 (162 g, 1.0 mol, 0.15 eq.) was dissolved in THF (800 mL) (caution, exothermic) under N2. This dark brown solution was cooled to ambient temperature using an ice bath and then added over 35 min to the 30 L reactor contents under N2 at an internal temperature of 10° C. To this yellow/green mixture, TMEDA (1.2 L) was added keeping the internal temperature below 20° C. (slightly exothermic). The resulting rust brown mixture was stirred at 45° C. for 1 h under N2. The reactor content was allowed to cool below 20° C. and a mixture of 1-bromo-2-(trifluoromethyl)benzene (1500 g, 6.67 mol) and bromocyclopentane (1192 g, 8.00 mol, 1.2 eq.) added dropwise under N2 at such a rate as to maintain the internal temperature between 25-30° C. (caution, exothermic). After the addition (3.33 h) and the exotherm subsided, the reaction mixture was stirred at 25° C. under N2 overnight, allowed to cool to an internal temperature of 0° C. and quenched with 6 NHCL (3 L, 1.5 h) at such a rate as to maintain the internal temperature below 15° C. (caution, very exothermic). After the quench, ethyl acetate (4 L) was added and the reactor content stirred at ambient temperature for 1 h. The phases were separated and the aqueous layer back extracted with ethyl acetate (2.5 L). The combined organic layers were washed with H2O (1 L), brine (1.5 L) and dried (Na2SO4). The solvent was rotary evaporated at 35° C. and the residue fraction distilled under high vacuum (65-70° C., 0.15 Torr) to give 823 g of product (58%, not wt % corrected) as a clear colorless liquid. 1H NMR (Bruker, 400 MHz, DMSO-d6) δ ppm 7.58-7.64 (m, 3H, ArH), 7.34-7.4 (m, 1H, ArH), 3.21-3.29 (m, 1H, —CH), 1.95-2.04 (m, 2H, —CH2), 1.76-1.88 (m, 2H, —CH2), 1.49-1.71 (m, 4H, —CH2).
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@:20]1([C:35]([OH:37])=[O:36])[CH2:25][CH2:24][CH2:23][O:22][C@@H:21]1[CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(CC)CC)C.O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:19][C@:20]1([C:35]([OH:37])=[O:36])[CH2:25][CH2:24][CH2:23][O:22][C@@H:21]1[CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1OCCC[C@]1(N)C(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H]1OCCC[C@]1(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.3 %

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (1.49 g, 5.98 mmol) was added to a solution of (2R*,3R*)-3-amino-2-(tert-butoxycarbonylamino)methyl-3,4,5,6-tetrahydro-2H-pyrane-3-carboxylic acid (1.09 g, 3.99 mmol) and triethylamine (1.11 mL, 7.96 mmol) in tetrahydrofuran (10 mL)/water (10 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate (150 mL) and washed with 1N hydrochloric acid (50 mL). The resulting organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=2:98→5:95) and then dissolved in a 1N sodium hydroxide solution (50 mL) and washed with diethyl ether (2×20 mL) to remove the remaining benzyl alcohol. The resulting aqueous layer was adjusted to pH 1 to 2 with concentrated hydrochloric acid, followed by extraction with dichloromethane (2×80 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. Then, the solvent was evaporated under reduced pressure to obtain 1.08 g (66%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8](Cl)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:5]=2[CH:4]=1)#[N:2].C(N(CC)CC)C.[H][H]>O1CCOCC1.[C].[Pd]>[C:1]([C:3]1[CH:19]=[CH:18][C:6]2[NH:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:5]=2[CH:4]=1)#[N:2]
Reactant: [H][H]
Reactant: N#Cc1ccc2nc(Cl)c3ccccc3c(=O)c2c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(c1)C(=O)c1ccccc1CN2
Yield: 46.2 %

Procedure:
The resulting 2-cyano-6-chloro-11-oxodibenz[b,e]azepine (17.4 g) and triethylamine (9 g) were dissolved in dioxane (840 ml), and the solution was catalytically hydrogenated for 17 hours at room temperature at a hydrogen pressure of 4 kg/cm2 with 10% palladium-carbon powder (2 g) as a catalyst. After the hydrogenation, the catalyst was filtered off, and the filtrate was concentrated at reduced pressure. The concentrate was purified by silica gel chromatography, and recrystallized from acetone to obtain 5,6-dihydro-2-cyano-11-oxodibenz[b,e]azepine (7.06 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:29])[CH3:6])[CH3:2]
Reactant: CCOC(=O)[C@@H](C)N1C(=O)COc2ccc(Br)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](C)N1C(=S)COc2ccc(Br)cc21
Temperature: 25 °C
Yield: 144.7 %

Procedure:
A solution of (R)-2-(6-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (82.4 g, 252 mmol) and Lawesson's reagent (61.1 g, 151 mmol) in toluene (900 mL) was heated at reflux for 3 h and then cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give (R)-2-(6-bromo-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (75.2 g, 87%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.19 (d, J=8.8 Hz, 1H), 7.04 (s, 1H), 6.93 (d, J=8.8 Hz, 1H), 6.57 (m, 2H), 4.96-4.87 (m, 2H), 4.29-4.16 (m, 2H), 1.71 (d, J=6.8 Hz, 3H), 1.18 (t, J=6.8 Hz, 3H). SFC (Table 1, Method 29) Rt=3.529 min.; [α]D20=19.25 (C=0.002 g/mL in methanol).