Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([N:15]([CH2:19]C)[CH2:16][CH2:17][NH2:18])C.[CH3:21][CH:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH3:23]>O1CCCC1.C(Cl)(Cl)Cl>[OH2:2].[CH3:19][N:15]([CH3:13])[CH2:16][CH2:17][NH:18][C:1](=[O:2])[N:24]([CH:22]([CH3:21])[CH3:23])[CH2:25][CH2:26][CH2:27][CH2:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:30])=[O:31]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CCN
Reactant: CC(C)NCCCCS(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)N(CCCCS(=O)(=O)c1ccccc1)C(=O)NCCN(C)C
Product: O
Yield: 74.9 %

Procedure:
A solution of 1,1'-carbonyldiimidazole (6.00 g, 0.037 mole) and N,N-diethylethylenediamine (4.00 g, 0.034 mole) was stirred at room temperature for 2 hours in 200 ml of tetrahydrofuran. A solution of N-(1-methylethyl)-4-[phenylsulfonyl]-1-butylamine (free base 7.99 g, 0.0313 mole) in 100 ml of tetrahydrofuran was added and the solution was heated overnight at reflux. The reaction was stripped to dryness and the residue dissolved in chloroform. The chloroform was extracted with water, dried (sodium sulfate), filtered, and removed in vacuo. A dark brown oil was obtained upon removal of chloroform. This oil was subjected to flash chromatography on Silica Gel using 0.1N ammonium hydroxide-methanol for elution. This chromatography furnished 5.37 g (42.2% yield) of clear oil after drying in vacuo 18 hours at 60° C. 1H NMR (CDCl3)δ7.8 (m, 5, aromatic), 5.25 (t, 1, NH), 4.15 (m, 1, methine), 3.2 (m, 6, SO2CH2 and methylenes adjacent to amide nitrogen, 2.5), (m, 6, ##STR28## 1.7 (m, 4, aliphatic--CH2CH2), 1.1 (m, 12, CH3).
Reaction SMILES: CO.C([N:10]1[CH2:15][CH2:14][O:13][CH:12]([C:16]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:27])[CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])[CH2:11]1)C1C=CC=CC=1.[ClH:34].C(O)C>[Pd].C(O)(C)C>[ClH:34].[F:24][C:22]1[CH:21]=[CH:20][C:19]([O:25][CH3:26])=[C:18]([CH2:17][C:16]([CH:12]2[O:13][CH2:14][CH2:15][NH:10][CH2:11]2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[OH:27])[CH:23]=1
Reactant: COc1ccc(F)cc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Solvent: CCO
Product: COc1ccc(F)cc1CC(O)(c1ccccc1)C1CNCCO1
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Alternatively, the following method may be used. A glass hydrogenation flask was loaded with methanol (1.55 L), Pd/C (10%, 31 g, 20% loading), 1-(4-benzyl-morpholin-2-yl)-2-(5-fluoro-2-methoxy-phenyl)-1-phenyl-ethanol (155 g, 0.368 mole) and a solution of HCl in ethanol (2.5N, 233 ml, 0.582 mole, 1.6 eq.). The reactor was mounted on a Parr instrument and pressurized with H2 (49 Psi). The reaction mixture was shaken overnight between 20° C. and 15° C. The catalyst was filtered off and washed with methanol (0.5 L). The filtrates were concentrated under vacuum. The yield of crude title compound was 109.5 g (81%). The catalyst was washed again with methanol (2×500 ml). The filtrates were combined and concentrated under vacuum. The yield of the second crop of crude title compound was 21.7 g (16%). A reactor was loaded with crude title compound (131 g, 0.356 mole) and isopropanol (1.3 L) under N2. The suspension was heated under reflux for 4 hours. The mixture was cooled to 20° C. and the solid was filtered, washed with isopropanol (130 ml), and dried at 50° C. under vacuum. The yield of pure title compound was 115.9 g (88.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH3:26])=[O:24].CN(C)C=O.CC1C=CC(S(O[CH2:43][C@@H:44]2[O:46][CH2:45]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH2:43][C@H:44]1[CH2:45][O:46]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[C:2]([Cl:1])[CH:7]=1)#[N:20]
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(C#N)cc23)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)cc1Cl
Temperature: 50 °C
Yield: 94 %

Procedure:
N-[2-Chloro-4-(6-cyano-7-hydroxyquinolin-4-yloxy)phenyl]-N′-methylurea (600 mg) was added to dimethylformamide (4 ml), and then (2R)-(−)-glycidyl p-toluenesulfonate (484 mg) and potassium carbonate (450 mg) were added thereto and the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized with ethyl acetate to obtain the title compound (650 mg) as light yellow crystals.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14]/[C:15]/2=C\C(O)=O)=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14]/[C:15]/2=[CH:1]\[C:2]([Cl:4])=[O:3])=[CH:10][CH:9]=1
Reactant: O=C(O)/C=C1\CCCc2ccc(F)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)/C=C1\CCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (3 ml, 0.034 mol, Aldrich) was added to a suspension of (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid (2.03 g, 0.01 mol) in toluene (35 ml) at 0° C. while protected from moisture by a nitrogen atmosphere. The stirring mixture was allowed to warm to 25° C. and was stirred for 1.5 h. Concentration in vacuo gave (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetyl chloride which was dissolved in dichloromethane and used without purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]([CH2:14][OH:15])[CH2:3]1.[C:16]([OH:22])([C:18]([F:21])([F:20])[F:19])=[O:17]>C(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:16]([OH:22])=[O:17].[OH:15][CH2:14][C@@H:4]1[NH:5][CH2:6][C@H:2]([OH:1])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC[C@H]1C[C@@H](O)CN1

Procedure:
1,1-Dimethylethyl(2R,4R)-4-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (0.185 g, 0.852 mmol) was stirred in a 1:1 solution of methylene chloride:TFA for 14 hours. The reaction was concentrated, and the crude material was used without further purification. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.5 (m, 1 H), 2.2 (m, 4 H), 3.0 (m, 1 H), 3.1 (m, 1 H), 3.6 (m, 3 H), 4.3 (m, 1 H), 5.3 (s,br, 2 H), 8.6 (s,br, 1 H), 9.2 (s,br, 1 H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][Zn+]>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: Clc1cccc(C[Zn+])c1
Agent: [Cl-]
Product: COC(=O)c1cc(Cl)cnc1Cc1cccc(Cl)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 58 from methyl 2,5-dichloronicotinate and 3-chlorobenzylzinc chloride: 1H-NMR (CDCl3) δ 8.65 (1H, d, J=2.6 Hz), 8.17 (1H, d, J=2.6 Hz), 7.26–7.12 (4H, m), 4.52 (2H, s), 3.89 (3H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:24][O:23][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=3)[N:7]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:6]2=[O:22])[O:4][CH2:3]1>CO.CCOC(C)=O.[Pd]>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:6](=[O:22])[C:5]12[O:23][CH2:24][C:2]([CH3:25])([CH3:1])[CH2:3][O:4]1
Reactant: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc(N)ccc21
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A mixture of methyl 2-(5,5-dimethyl-5′-nitro-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (344 mg, 0.982 mmol) and 10% w/w Pd/C (cat. amount) in MeOH/EtOAc 1:1 (50 ml) was hydrogenated at 15 psi in a Parr apparatus for 2 hours. The catalyst was removed by filtration, and the residue was evaporated affording crude methyl 2-(5′-amino-5,5-dimethyl-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (307 mg, 0.958 mmol, 98% yield) that was used in the following step without further purification. MS/ESI+ 321.0 [MH]+
Reaction SMILES: [CH2:1]([C@H:8]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:9][C@H:10]([OH:40])[C@@H:11]([N:25](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.C(OCC)(=O)C.O1CCOCC1.[OH-].[OH-].[Pd+2]>[NH2:25][C@@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C@@H:10]([OH:40])[CH2:9][C@@H:8]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccc(-c2ccccn2)cc1
Temperature: 60 °C

Procedure:
Method 2 A solution containing the product from Example 23P (2.7 g, 4.21 mmol) in a mixture of methanol (20 mL) and ethyl acetate (20 mL) was treated with 20% Pd(OH)2 on carbon (1 g) and an HCl solution in dioxane (2 mL, 4 N), stirred under an atmosphere of hydrogen (balloon pressure) for 16 hours at 25° C., heated to 60° C. for 6 hours. The reaction cooled and filtered through celite®, and concentrated. The residue was partitioned between dichloromethane and half-saturated NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35]([NH2:37])=[O:36])O1.C([O-])([O-])=O.[Na+].[Na+]>O.O1CCOCC1.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>[CH3:23][O:22][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=3)[C:35]([NH2:37])=[O:36])[N:3]=2)[CH:17]=[C:16]([O:18][CH3:19])[C:15]=1[O:20][CH3:21]
Reactant: CC1(C)OB(c2cccc(C(N)=O)c2)OC1(C)C
Reactant: COc1cc(Nc2nc(Cl)nc3scnc23)cc(OC)c1OC
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nc(-c3cccc(C(N)=O)c3)nc3scnc23)cc(OC)c1OC
Temperature: 97 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
To a stirred solution of 5-chloro-N-(3,4,5-trimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (337 mg, 0.95 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (190 mg, 1.15 mmol) and Na2CO3 (347 mg, 3.27 mmol) in 2 mL of water and 50 mL of dioxane was added Pd(PPh3)4 (100 mg, 0.086 mmol) in one portion at room temperature under nitrogen. Then the mixture was stirred at 97° C. for 16 hours under nitrogen. The solvent was evaporated at 40° C. at reduced pressure and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:2)) to give a crude product. It was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 20% acetonitrile/80% water (0.1% TFA V/V) initially, and then proceed to 45% acetonitrile/55% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3,4,5-trimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (120 mg, 27.4%) as a solid. 1H NMR (300 MHz, DMSO): δ 10.10 (s, 1H), 9.43 (s, 1H), 8.93 (s, 1H), 8.58 (d, 1H, J=8.1 Hz), 8.03-8.00 (m, 2H), 7.65-7.60 (m, 3H), 7.50 (brs, 1H), 3.87 (s, 3H), 3.71 (s, 3H), 3.30 (s, 3H). LC-MS: 438 [M+H]+, tR=1.43 min. HPLC: 99.77% at 214 nm, 99.84% at 254 nm, tR=5.68 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]=O)=[N:4][CH:5]=[C:6]([N:8]([CH:10]2[CH2:13][CH2:12][CH2:11]2)[CH3:9])[N:7]=1.[CH2:16]([NH:23][CH2:24][C@@H:25]([OH:29])[CH2:26][O:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:16]([N:23]([CH2:14][C:3]1[C:2]([Cl:1])=[N:7][C:6]([N:8]([CH:10]2[CH2:11][CH2:12][CH2:13]2)[CH3:9])=[CH:5][N:4]=1)[CH2:24][C@@H:25]([OH:29])[CH2:26][O:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(c1cnc(C=O)c(Cl)n1)C1CCC1
Reactant: COC[C@H](O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC[C@H](O)CN(Cc1ccccc1)Cc1ncc(N(C)C2CCC2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 3-chloro-5-[cyclobutyl(methyl)amino]pyrazine-2-carbaldehyde (451 mg), (2R)-1-(benzylamino)-3-methoxypropan-2-ol (469 mg) and acetic acid (343 μL) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (636 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added dropwise a saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (674 mg, 83%).
Reaction SMILES: [CH2:1]([NH:5][C:6]([N:8]1[CH:12]=[CH:11][NH:10][C:9]1=[S:13])=[O:7])[CH2:2][CH2:3][CH3:4].BrBr.C(N(CC)CC)C>ClCCl>[CH2:1]([N:5]1[C:6](=[O:7])[N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[S:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)n1cc[nH]c1=S
Agent: BrBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCn1sc2nccn2c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To solution containing 1-(butylcarbamoyl)-1,3-dihydroimidazole-2-thione (4.73 g, 23.7 mmole) suspended in 15 mL of dichloromethane cooled to 0° C. under a nitrogen atmosphere, was added bromine (3.79 g, 23.7 mmole) dissolved in 15 mL of dichloromethane, in a dropwise manner. After the addition was complete, triethylamine (4.81 g, 47.5 mmole) dissolved in 15 mL dichloromethane was added such that the temperature of the reaction mixture never exceeded 0° C. The reaction mixture was maintained at 0° C. for an additional 2 h and then stirred for 16 h at room temperature. It was then diluted with 150 mL of dichloromethane and washed twice with water and once with a saturated sodium chloride solution. The organic layer was then dried over magnesium sulfate and evaporated to dryness to yield 4.30 g (92%) of 2-butylimidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-one as an off-white powder: mp 142°-143° C.; 1H NMR (CDCl3) δ7.40 (d, 1H), 7.20 (d, 1H), 3.79 (t, 2H), 1.73 (m, 2H), 1.40 (m, 2H), 0.957 (t, 3H) ppm; IR (KBr) ν1702 cm-1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][C@H:11]([C:13]1[N:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15](=[O:24])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[CH3:12].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH3:12])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N[C@@H](C)c2cc3cccc(Cl)c3c(=O)n2-c2ccccc2)nc(N)n1
Temperature: 160 °C

Procedure:
To a stirred mixture of 2-amino-4-chloro-6-methylpyrimidine (0.266 mmol, 1.62 eq) and compound 1 (0.164 mmol, 0.164 mmol, 1 eq) in NMP (1.5 ml), DIPEA (0.656 mmol, 4 eq) was added. The mixture was heated to 160° C. for 12 hours. Then the mixture was extracted with ethyl acetate and washed with water and brine. The product was purified by silica gel column chromatography eluting with DCM/methanol (from 0 to 10%) to afford the product (S)-3-(1-((2-amino-6-methylpyrimidin-4-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one 92. ESI-MS m/z: 406.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[S:20][C:21](Br)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>CCOC(C)=O.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.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[S:20][C:21]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:33]=3)=[CH:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1ccc(Br)s1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(-c2ccc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)s2)c1
Yield: 73.1 %

Procedure:
In a 5 ml glass tube were placed 5-bromo-thiophene-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.12 mmol), 3-isopropyl phenyl boronic acid (37 mg, 0.23 mmol), Cs2CO3 (114 mg, 0.34 mmol), Pd(PPh3)2Cl2 (6.4 mg, 0.009 mmol), DME (0.8 mL), ethanol (0.2 mL), and a magnetic stir bar. The vial was sealed with septum and placed into the Microwave cavity. The vial was irradiated in a Microwave synthesizer at 140° C. for 20 min. The mixture was diluted with EtOAc and washed with 1N HCl and water. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give title compound (42 mg, 77%).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[F:19])[N:3]=1.[IH:20].[Na+].[I-]>O>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:4]2[N:3]=[C:2]([I:20])[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[N:5]=2)[CH:17]=1
Reactant: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)CCCC2
Reactant: I
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(Cl)cc1-c1nc(I)c2c(n1)CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (534 mg, 1.89 mmol, 1 eq) in a 57% HI solution in water (10 ml) at r.t. was added NaI (1.42 g, 9.47 mmol, 5 eq). The reaction mixture was stirred at r.t. overnight and then poured onto ice. The product was extracted with chloroform and the aqueous layer was neutralized with NaHCO3 and extracted further with more chloroform. The organic layers were combined, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude white solid 2-(5-Chloro-2-fluorophenyl)-4-iodo-5,6,7,8-tetrahydroquinazoline which was not further purified.
Reaction SMILES: [Br:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].O.N>C(O)C.S([O-])([O-])(=O)=O.[Fe+2]>[Br:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7]
Reactant: O=C1OCc2c1ccc([N+](=O)[O-])c2Br
Agent: [Fe+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1Br)COC2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
6.6 g of 4-bromo-5-nitrophthalide is dissolved in 45 ml of ethanol and added in drops to a mixture of 65 g of iron(II) sulfate, 220 ml of water and 65 ml of ammonia (33%) that is heated to 60° C. and thoroughly stirred. After 2 hours at 60° C., the mixture is absorptively precipitated five times with 200 ml of diethyl ether. The diethyl ether phases are concentrated by evaporation. As a residue, 4.1 g of 4-bromo-5-aminophthalide is obtained, flash point 176-180° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2].N1C=CN=C1.[CH:26]([Si:29](Cl)([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])([CH3:28])[CH3:27].O>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si:29]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:26]([CH3:28])[CH3:27])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2nccc(C)c21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (10 g) and 1H-imidazole (3.79 g) in DMF (100 mL) was added triisopropylsilyl chloride (9.54 mL) at 0° C. The mixture was stirred at room temperature for 3 days, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/Hexane=1/10) to give the title compound (11.5 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10](=[O:21])[CH:9]1[CH:22]([C:24]1[N:28]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)[CH:27]=[N:26][CH:25]=1)[OH:23])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[ClH:20].[Cl:20][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH:9]([CH:22]([C:24]3[N:28]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([C:36]#[N:37])=[CH:34][CH:35]=4)[CH:27]=[N:26][CH:25]=3)[OH:23])[C:10]2=[O:21])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2)C(=O)C1C(O)c1cncn1Cc1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N#Cc1ccc(Cn2cncc2C(O)C2NCCN(c3cccc(Cl)c3)C2=O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the piperazinone from Step J (60 mg, 0.115 mmol) in 2 mL of dichloromethane at 0 ° C. was added trifluoroacetic acid (1.0 mL), and the reaction was allowed to warm to room temperature. After 6 hours, the solution was concentrated in vacuo, taken up in CH2Cl2, washed with dilute aq. NaHCO3 soln., dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. After conversion to the HCl salt, the product was isolated (62 mg) as a 9:1 mixture of diastereomers. FAB ms: 422 (M+1). Anal. Calc for C22H20ClN5O2.2.10 HCl. 1.00 H2O: C, 51.16; H, 4.70; 0, 13.56. Found: C, 51.21; H, 4.70; 0, 12.66.