Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[H][H]>[Pd].O1CCOCC1>[CH2:1]([CH:2]1[C:10]2[C:11](=[O:12])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[C:9]=2[CH2:11][CH2:4][CH2:3]1)[CH2:6][CH2:5][CH3:7]
Reactant: [H][H]
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCCC1CCCC2=C1C(=O)c1ccccc1C2=O
Reaction time: 3 h
Yield: 59 %

Procedure:
A solution of 78.0 g. (0.495 mole) naphthoquinone and 56.0 g. (0.52 mole) butadienedimer in 200 ml. dioxane was heated at 90°-95°C. for one hour, and then at 80°-90°C. for 3 hours. The solution was then cooled and 2.0 g. 10% palladium-on-charcoal (Pd/C) catalyst added. The mixture was then hydrogenated at 42 psi until the theoretical amount of hydrogen was taken up. After removal of the catalyst by filtration and addition of 2 ml. DBN, a slow stream of air was blown through the solution for six hours. The solution was then poured into 2000 ml. water and the mixture extracted three times with 300 ml., 100 ml. and 100 ml. portions of cyclohexane. The combined cyclohexane extracts were dried over anhydrous potassium carbonate, treated with Darco activated charcoal (Atlas Chemical Industries), and then filtered. After removal of the solvent by using a steam bath, 73.0 g. of crude product was obtained (59% yield). The product was purified by chromatography on acidic alumina using cyclohexane eluent. An analytical sample, after recrystallization from methanol, had m.p. 64°-65°C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N+:11]([O-])=O)[C:5]([CH3:14])=[N:4]1)[CH3:2].Cl>C(O)C.O.[Fe]>[NH2:11][C:6]1[C:5]([CH3:14])=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[C:8]([NH2:10])=[O:9]
Reactant: CCn1nc(C)c([N+](=O)[O-])c1C(N)=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCn1nc(C)c(N)c1C(N)=O

Procedure:
A mixture of 20 g (0.1 mol) of the above amide in 150 ml of ethanol and 30 ml of water containing 3 ml of conc. HCl is stirred under reflux with 25 g of iron powder for three hours and filtered warm using filter-cell. The filtrate is evaporated in vacuo to yield a pink solid, mp 143°-145° C. (from ethyl acetate-pet. ether) of 4-amino-1-ethyl-3-methylpyrazole-5-carboxamide. The reaction of this aminopyrazole with 18 ml acetic anhydride in 250 ml of methylene dichloride gives 18.5 g of N-(1-ethyl-5-carboxamido 3-methylpyrazol-4-yl)acetamide, mp 248°-250° C.
Reaction SMILES: N[C:2]([C:6]1[S:7][C:8]([Cl:11])=[CH:9][CH:10]=1)=[CH:3][C:4]#[N:5].Cl.C[OH:14]>>[Cl:11][C:8]1[S:7][C:6]([C:2](=[O:14])[CH2:3][C:4]#[N:5])=[CH:10][CH:9]=1
Reactant: N#CC=C(N)c1ccc(Cl)s1
Reactant: CO
Agent: Cl
Product: N#CCC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 9.2 g. portion of β-amino-5-chloro-2-thiopheneacrylonitrile is dissolved in 100 ml. of methanol. A 50 ml. portion of 1 N hydrochloric acid is added and the mixture is stirred at room temperature for 3 hours. The precipitate is collected giving 5-chloro-β-oxo-2-thiophenepropionitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:15][C@H:16]1[O:21][C@@H:20]([CH2:22][N:23]2C(=O)C3=CC=CC=C3C2=O)[CH2:19][CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:5])[CH3:2].O.NN>CO>[NH2:23][CH2:22][C@H:20]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH2:15][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[O:21]1
Reactant: CCOC(=O)N(Cc1ccc(F)cc1)C[C@@H]1CCC[C@H](CN2C(=O)c3ccccc3C2=O)O1
Agent: NN
Solvent: CO
Solvent: O
Product: CCOC(=O)N(Cc1ccc(F)cc1)C[C@@H]1CCC[C@H](CN)O1
Yield: 99.6 %

Procedure:
To a solution of the crude cis-6-[N-ethoxycarbonyl-N-(p-fluorobenzyl)aminomethyl]-2-phthalimidomethyltetrahydropyrane (2.81 g, 6.19 mmol) in methanol (30 ml) was added hydrazine monohydrate (0.48 ml, 15 mmol) and heated under reflux for 2 hours. To the reaction mixture was added purified water (30 ml) to dissolve insolubles and the ethanol was distilled off under reduced pressure. The aqueous layer was extracted with chloroform (50 ml×3). The combined organic layer was dried over potassium carbonate and the solvent was distilled off under reduced pressure to give crude cis-2-aminomethyl-6-[N-ethoxycarbonyl-N-(p-fluorobenzyl)aminomethyl]tetrahydropyrane (2.0 g). This compound was used for the subsequent reaction without purification. Yield of two steps=100%.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:20]([NH:22][C@H:23]([C:41]([N:43]1[CH2:82][CH2:81][CH2:80][C@H:44]1[C:45]([NH:47][C@H:48]([C:50]([NH:52][C@H:53]([C:70]([O:72]CC1C=CC=CC=1)=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][NH:58]C(OCC1C=CC=CC=1Cl)=O)=[O:51])[CH3:49])=[O:46])=[O:42])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:40])[NH:29]S(C1C=CC(C)=CC=1)(=O)=O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8]S(C1C=CC(C)=CC=1)(=O)=O.C1(OC)C=CC=CC=1>>[NH2:1][C@H:2]([C:20]([NH:22][C@H:23]([C:41]([N:43]1[CH2:82][CH2:81][CH2:80][C@H:44]1[C:45]([NH:47][C@H:48]([C:50]([NH:52][C@H:53]([C:70]([OH:72])=[O:71])[CH2:54][CH2:55][CH2:56][CH2:57][NH2:58])=[O:51])[CH3:49])=[O:46])=[O:42])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:29])[NH2:40])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:19]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)NS(=O)(=O)c2ccc(C)cc2)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Solvent: COc1ccccc1
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](CCCCN)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
The solution of 280 mg (0.188 mmol) of Boc-Arg(Tos)-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 18), 1 ml of anisole and 2 ml of HF was stirred at 0° C. for 2 h. The reaction mixture was evaporated under reduced pressure to remove HF. To the residue 2 ml of HF were added and the solution was stirred at 0° C. for another 1 h. The reaction mixture was evaporated under reduced pressure to remove HF. The residue was triturated with ether and the resulted solid was purified on the Sephadex G-10 column. The collected fractions were lyophilized to provide 100 mg (85%) of the title compound. Mp. 168–170° C., FAB-MS (m/e) 627[M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[O:12][C:11](=[O:13])[NH:10][N:9]=1.[Cl:14][C:15]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18]>C(#N)C>[Cl:14][C:15]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:16]=1[C:17]([NH:19][C:20]([NH:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[O:12][C:11](=[O:13])[NH:10][N:9]=1)=[O:21])=[O:18]
Reactant: Nc1ccsc1-c1n[nH]c(=O)o1
Reactant: O=C=NC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Solvent: CC#N
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1ccsc1-c1n[nH]c(=O)o1
Reaction time: 3 h

Procedure:
5-(3-Aminothiophen-2-yl)-3H-[1,3,4]oxadiazol-2-one hydrochloride (30 mg) is initially charged in 3 ml of acetonitrile. The equimolar solution of 2-chloro-4,5-difluorobenzoyl isocyanate in acetonitrile is added. After 3 hours, the solid is filtered off with suction and dried under reduced pressure.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47](Cl)(=[O:52])[CH2:48][CH2:49][CH2:50][CH3:51].C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:52])[CH2:48][CH2:49][CH2:50][CH3:51])[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added pentanoyl chloride (0.060 g, 0.496 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between ethyl acetate and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 687 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([C:14]#[N:15])[CH:8]=[C:9]([O:12]C)[CH:10]=2)[C:5](=[O:16])[N:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[CH:3]=1.B(Br)(Br)Br>O>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([C:14]#[N:15])[CH:8]=[C:9]([OH:12])[CH:10]=2)[C:5](=[O:16])[N:4]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:3]=1
Reactant: COc1ccc(-n2cc(Br)c3cc(OC)cc(C#N)c3c2=O)cc1
Agent: BrB(Br)Br
Solvent: O
Product: N#Cc1cc(O)cc2c(Br)cn(-c3ccc(O)cc3)c(=O)c12
Temperature: 25 °C
Yield: 36 %

Procedure:
4-Bromo-6-methoxy-2-(4-methoxyphenyl)-1-oxo-1,2-dihydroisoquinoline-8-carbonitrile (0.15 g, 0.39 mmol) was placed in a dry and argon flushed 100 mL single-necked round-bottomed flask fitted with a stirring bar, reflux condenser and an argon inlet. Anhydrous chlorobenzene (10 mL) was added via a syringe at room temperature. BBr3 (0.59, 2.33 mmol) was added via a syringe with stirring at room temperature. The resulting solution was heated to 120° C. for 4 hours. 10 mL of water was added to quench the reaction. After stirred at room temperature for one hour, the solution was extracted with EtOAc (5×20 mL). The organic layers were combined and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica-gel, CH2C2/MeOH=9/1 v/v) to give a white solid product, 0.05 g, 36.0% yield. M.p. ° C. (decomposed). MS: m/z 357.1 [M+H]+. 1H NMR (DMSO-d6, 300 MHz) δ 11.40 (s, 1H), 9.79 (s, 1H), 7.91 (s, 1H), 7.48 (d, 1H, J=2.1 Hz), 7.38 (d, 1H, J=2.1 Hz), 7.26 (d, 2H, J=8.7 Hz), 6.86 (d, 2H, J=8.7 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6](=[O:17])[NH:5]2.F[C:19]1C=C2C(NC(=O)C(C(OCC)=O)=N2)=C[CH:20]=1.C(I)C.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:19]([N:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]1=[O:17])[CH3:20]
Reactant: CCOC(=O)c1nc2ccc(F)cc2[nH]c1=O
Reactant: CCOC(=O)c1nc2cc(F)ccc2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCI
Product: CCOC(=O)c1nc2ccc(F)cc2n(CC)c1=O

Procedure:
The mixture of 6-fluoro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester and 7-fluoro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (Example 22a) (2 g), ethyl iodide (4 g) and anhydrous potassium carbonate (5.9 g) in 2-butanone (200 ml) were heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated. The residual oil was chromatographed on silica using a mixture of petroleum ether (b.p. 60°-80°) and ethyl acetate (3:1) as eluent to give the required product, on evaporation of the later fractions, m.p. 99°-101.5°, (50%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].BrC1C=C2C(CCCC2(C)C)=CC=1>>[C:1]([C:3]1[CH:4]=[C:5]2[C:10]([CH2:9][CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])=[CH:11][CH:12]=1)#[CH:2]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Agent: CC1(C)CCCc2ccc(Br)cc21
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2

Procedure:
Employing the same general procedure as for the preparation of 6-ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound K), 2.1 g (8.8 mmol) of 7-bromo-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene was converted into the title compound using 10 ml (93.9 mmol) of trimethylsilyl acetylene, 1.25 g (1.8 mmol) of bis (triphenylphosphine) palladium (II) chloride, 0.53 g (2.8 mmol) of cuprous iodide and 10 ml (20.0 mmol) of K2CO3 (2M solution in methanol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Cl[C:29]1[N:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[N:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Clc1cccnn1
Product: C[C@@H](c1ccc(-c2cccnn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 3-chloropyridazine in Step 4. LC-MS Method 2 tR=1.067, m/z=436.1; 1H NMR (CDCl3) 0.82 (m, 3H), 1.52 (d, 3H), 1.65 (m, 1H), 1.80-1.98 (m, 2H), 2.11-2.28 (m, 3H), 2.91 (m, 1H), 3.51 (t, 3H), 5.68 (m, 1H), 6.94-7.04 (m, 4H), 7.18 (m, 2H), 7.47 (m, 1H), 7.71 (d, 1H), 7.78 (d, 2H), 9.08 (d, 1H).
Reaction SMILES: C([N:8]1[C:12]2[C:13](=[O:37])[N:14]([CH3:36])[CH:15]=[C:16]([C:17]3[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=3[O:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])[C:11]=2[CH:10]=[C:9]1[C:38]([O:40][CH2:41][CH3:42])=[O:39])C1C=CC=CC=1.C1(OC)C=CC=CC=1.S(=O)(=O)(O)O.FC(F)(F)C(O)=O>>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[O:27][C:18]1[CH:19]=[CH:20][C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:22][C:17]=1[C:16]1[C:11]2[CH:10]=[C:9]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[NH:8][C:12]=2[C:13](=[O:37])[N:14]([CH3:36])[CH:15]=1
Reactant: CCOC(=O)c1cc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c(=O)c2n1Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)c1cc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c(=O)c2[nH]1
Yield: 63 %

Procedure:
A mixture of Example 252e, anisole (1.585 mL, 14.51 mmol) and concentrated sulfuric acid (4.3 mL, 81 mmol) in trifluoroacetic acid (20 mL, 260 mmol) was heated at 90° C. for 4 hours. Excess trifluoroacetic acid was removed under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate (2×200 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (100 mL), followed by saturated aqueous sodium chloride (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material was taken into methanol (50 mL) and the resulting solid was filtered, rinsed with methanol, and dried to provide the title compound (3.1 g, 63% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl>[C:17]([O:16][C:14]([N:13]1[CH2:12][C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]1[CH2:4][C:3]([O:2][CH3:1])=[O:21])=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: COC(=O)C=Cc1ccccc1CNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1c2ccccc2CN1C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 45 %

Procedure:
To a 0° C. solution of (116.9 g, 401.2 mmol) material from Step B in DCM (800 mL) was added 200 mL of TFA dropwise over 15 minutes. After removing the cooling bath, the mixture was stirred for about 2.5 hours and then concentrated to dryness. The residue was dissolved in 500 mL of DCM and saturated aqueous sodium bicarbonate is slowly added until the mixture was slightly basic. The organic portion was separated and the aqueous portion is extracted two times with DCM. The combined organic portions were dried (Na2SO4) and concentrated to dryness. The residue was dissolved in 800 mL of DCM and DIPEA (57.0 g, 441.4 mmol) was added. To the mixture was added di-tert-butyl dicarbonate (96.3 g, 441.4 mmol) in five portions over 45 minutes and then stirred at r.t. for 16 hours. The mixture was washed with 10% aqueous sodium bisulfate, and the organic portion was separated and the aqueous portion is extracted two times with DCM. The combined organic extracts were dried ((Na2SO4) and concentrated to dryness. The resulting residue was dissolved in a small amount of DCM and filtered through 7 inch silica gel in a 2L sintered glass funnel eluting with 25% EtOAc/hexanes. The eluent was concentrated to dryness and the enantiomers were separated by chiral chromatography. The first eluting isomer was labeled as isomer #1 and the second eluting is labeled as isomer #2, which afforded about 52.6 g (45%) of the final compound (isomer 2). EIS-MS 292 [M+1].
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1.N([O-])=O.[Na+].[Cl-:24].N>Cl.O.CC(C)=O>[Cl:19][C:16]1[CH:17]=[CH:18][C:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:24])=[CH:7][N:6]=2)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: [Cl-]
Reactant: COC(=O)c1cc(Cl)ccc1Oc1ccc(N)cn1
Agent: Cl
Agent: N
Agent: O=N[O-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1Oc1ccc(Cl)cn1
Temperature: 0 °C
Yield: 32.3 %

Procedure:
To a solution of methyl 2-[(5-aminopyridin-2-yl)oxy]-5-chlorobenzoate (step 2 of Example 101, 1.00 g, 3.6 mmol) in 0.66 M hydrochloric acid (11 mL) was added sodium nitrite (252 mg, 3.6 mmol) in water (5 mL) at 0° C. The reaction mixture was stirred for 30 mim at 0° C. The mixture was added dropwise to a stirred suspension of cupper(II) chloride (1.21 g, 9.0 mmol) in acetone (18 mL) and water (5.4 mL). The whole was stirred at 50° C. for 30 min. Then the reaction mixture was poured into water and it was added ammonia solution. The aqueous mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (20/1) to afford 347 mg (32%) of the title compound: 1H-NMR (CDCl3) δ 8.00 (1H, d, J=2.8 Hz), 7.99 (1H, d, J=2.8 Hz), 7.67 (1H, dd, J=8.7, 2.8 Hz), 7.55 (1H, dd, J=8.6, 2.8 Hz), 7.14 (1H, d, J=8.6 Hz), 6.97 (1H, d, J=8.7 Hz), 3.72 (3H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[S:13](Cl)(Cl)=[O:14]>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][N:4]1[CH2:3][CH2:2][O:1][S:13]1=[O:14]
Reactant: O=S(Cl)Cl
Reactant: OCCNCc1ccccc1Cl
Product: O=S1OCCN1Cc1ccccc1Cl

Procedure:
contacting N-hydroxyethyl-2-chlorobenzylamine with thionyl chloride and an organic base to give N-(2-chlorobenzyl)-2-oxo-1,2,3-oxathiazolidine, and
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]2([CH3:15])[CH2:14][CH2:13]2)[CH:11]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([O:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]([NH2:50])=[CH:42][N:41]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C.ClCCl>CS(C)=O.O>[C:26]([O:30][C:31]([N:33]1[CH2:34][CH2:35][CH:36]([O:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]([NH:50][C:5]([NH:6][C:7]3[N:8]([C:16]4[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=4)[N:9]=[C:10]([C:12]4([CH3:15])[CH2:13][CH2:14]4)[CH:11]=3)=[O:4])=[CH:42][N:41]=2)[CH2:37][CH2:38]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncc(N)c3ccccc23)CC1
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 59.1 %

Procedure:
Dissolve [5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Preparation 18, 3.20 g, 7.94 mmol and 2.0 equiv) and 4-(4-amino-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 22, 1.37 g, 3.97 mmol, 1.0 equiv) in 7 mL of anhydrous DMSO, add diisopropylethyl amine (DIPEA, 1.36 mL, 7.94 mmol, 2.0 equiv) and heat in a sealed tube with stirring for 20 hours at 80° C. Pour the solution in a 1:1 v/v mixture of dichloromethane and iced water. Extract the aqueous phase with dichloromethane (2×50 mL), and wash the combined organic layers with water (2×50 mL) and aqueous sodium chloride (100 mL). Dry the organic solution over sodium sulfate and evaporate under reduced pressure. Subject residue to silica gel chromatography eluting with a gradient from 15% to 80% EtOAc in hexanes to afford 1.40 g of 4-(4-{3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester as a pure foamy cream solid. 59% yield. ES+ (m/z) 597.4 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][C:5]([C:8]([OH:10])=O)=[CH:6][N:7]=1.Cl.[NH2:12][C@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)=[CH:23][CH:22]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.O.CCOC(C)=O>[Cl:33][C:29]1[CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C@@H:13]([NH:12][C:8]([C:5]3[S:4][C:3]([O:2][CH3:1])=[N:7][CH:6]=3)=[O:10])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:22][CH:23]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COc1ncc(C(=O)O)s1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cnc(OC)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of 2-methoxythiazole-5-carboxylic acid (80 mg, 0.50 mmol) and (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (160 mg, 0.45 mmol) in DMF (5 mL) is added HATU (207 mg, 0.55 mmol) and TEA (276 mg, 2.73 mmol). The crude is stirred at room temperature for 2 hrs. The crude is neutralized with 1 N HCl and diluted in water and EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. The crude is purified via flash chromatography using 30% EtOAc/heptane to 70% EtOAc/heptane to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-methoxythiazole-5-carboxamido)butanoate (170 mg). HPLC retention time=1.97 minutes (condition D); MS (m+1)=459.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.1 Hz, 3 H) 2.49-2.69 (m, 2 H) 2.93 (dd, J=13.6, 8.1 Hz, 1 H) 3.10 (dd, J=13.5, 6.2 Hz, 1 H) 4.09 (s, 3 H) 4.00-4.15 (m, 2 H) 4.53-4.69 (m, 1 H) 6.78 (d, J=8.6 Hz, 1 H) 7.25-7.32 (m, 3 H) 7.35 (t, J=7.71 Hz, 1 H) 7.44 (dt, J=7.6, 1.5 Hz, 1 H) 7.48-7.54 (m, 3 H) 7.55 (t, J=1.8 Hz, 1 H).