Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH:30]=2)[S:16]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])(=[O:18])=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH:30]=2)[S:16]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])(=[O:18])=[O:17])=[CH:13][CH:14]=1
Reactant: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(OCc3ccccc3)cc2)c(C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(OC3CCCCO3)c2)c2ccc(O)cc2)c(C)c1
Yield: 0.1 %

Procedure:
To a solution of N-(4-benzyloxy-phenyl)-2,4,6-trimethyl-N-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide (7.39 g, 12.9 mol) in 300 mL methanol was added palladium black (0.800 g) and ammonium formate (8.15 g, 129 mmol). The reaction mixture was heated at reflux for 3 hr. and was cooled. The reaction mixture was filtered through diatomaceous earth with the aid of methanol (2×50 mL). The filtrate was concentrated and the residue was partitioned between 600 mL ethyl acetate and 250 mL water. The layers were separated and the organic layer was washed with water (2×300 mL) and saturated aqueous sodium chloride (1×300 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography (25% ethyl acetate/hexanes) afforded 5.00 g of the title compound of Step D. MS 482.2 (M+1)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(F)c(F)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3,4-difluoro-phenylboronic acid to give [1-(3,4-difluoro-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[CH:9][N:8]=1.C([Li])CCC.CN(C)C=O>O>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[C:10]1[CH:11]=[CH:12][C:7]([CH:2]=[O:1])=[N:8][CH:9]=1
Reactant: Brc1ccc(C2OCCO2)cn1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(C2OCCO2)cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a tetrahydrofuran (100 mL) solution of 2-bromo-5-[1,3]dioxolan-2-yl-pyridine (4.77 g, 20.7 mmol) described in Manufacturing Example 154-1-2 was added n-butyl lithium (14.3 mL, 1.6 M hexane solution, 22.8 mmol) under nitrogen atmosphere at −78° C., which was stirred for 20 minutes at −78° C. Then, N,N-dimethylformamide (1.92 mL, 24.8 mmol) was added to the reaction mixture, which was stirred for 15 minutes while the temperature was raised to room temperature. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (1.73 g, 47%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:17][CH:16]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-hydroxyphthalimide (11.1 g) and p-methoxybenzyl bromide (13.7 ml) in N,N-dimethylformamide (100 ml) is added triethylamine (6.8 g), and the mixture is stirred at room temperature for 1 hour and at 60° to 70° C. for 1 hour. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract solution is washed with diluted hydrochloric acid and water, dried and concentrated under reduced pressure. The residue is crystallized from methanol to give N-p-methoxybenzyloxyphthalimide (17 g). mp. 139°-141° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14](O)=O)#[CH:2].CCN(C(C)C)C(C)C.[NH2:26][C:27]1[C:28](=[O:40])[N:29]([CH3:39])[C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=1[NH2:33]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][C:14]1[NH:26][C:27]2[C:28](=[O:40])[N:29]([CH3:39])[C:30](=[O:38])[N:31]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:32]=2[N:33]=1)#[CH:2]
Reactant: C#Cc1ccc2cncc(CC(=O)O)c2c1
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#Cc1ccc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(6-Ethynyl-isoquinolin-4-yl)-acetic acid (58 mg, 0.28 mmol) is dissolved in DMF (1 ml) and O-(7-azabenzotriazo-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.125 g, 0.33 mmol) and Hunig's base (0.180 ml, 1.03 mmol) are added, followed by a solution of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (58 mg, 0.28 mmol) in DMF (0.7 ml). The reaction is stirred at room temperature for 2 hours. The solvent is evaporated and the residue purified by flash column chromatography (30:1 dichloromethane-methanol elution). The intermediate is dissolved in methanol (2 ml) and water (2.75 ml) added, followed by 4M aqueous sodium hydroxide (0.25 ml). The reaction is heated at 40° C. for 2 hours, then stirred for 16 hours at ambient temperature. The solvent is evaporated and the crude product purified by flash column chromatography (30:1 dichloromethane-methanol elution) to afford 8-(6-ethynyl-isoquinolin4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione, [MH]+ 388.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:12]=2)[CH:7]=1
Reactant: Cc1cncc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)c1
Yield: 46.9 %

Procedure:
A mixture of 3-methyl-5-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine from step 4 (3.8 g, 9.5 mmol) and p-toluenesulfonic acid monohydrate (0.91 g, 4.8 mmol) in 150 mL of toluene was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was partitioned between water and methylene chloride. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and the crude product was purified by flash chromatography on silica gel (ethyl acetate/acetone, 98:2) to give 3-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine as a yellow solid (1.7 g, 47%): mp (DSC) 196-198° C.; Anal. Calc'd. for C17H14F3N3O2S: C, 53.54, H, 3.70, N, 11.02, S, 8.41. Found: C, 53.50, H, 3.65, N, 10.82, S, 8.55.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH:45]1[CH2:49][CH2:48][CH:47]([OH:50])[CH2:46]1>C(#N)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:44])[N:5]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=3)[C:6](=[O:33])[N:7]2[C:21]([N:45]2[CH2:49][CH2:48][CH:47]([OH:50])[CH2:46]2)=[O:22])=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=1)#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OC1CCNC1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)N2CCC(O)C2)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (78.0 mg, 0.125 mmol; Example 6A) was reacted with pyrrolidin-3-ol (32.6 mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound (58 mg, 81% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[C:14]([CH3:30])=[N:15][C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=3[O:11][N:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:38])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Br:38][CH2:30][C:14]1[C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:10][O:11][C:12]=2[C:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(C)c2c(-c3ccc(OC)cc3)noc2c1OC(=O)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(CBr)c2c(-c3ccc(OC)cc3)noc2c1OC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 49.4 %

Procedure:
Ethyl 3-(4-methoxyphenyl)-4-methyl-7-(pivaloyloxy)isoxazolo[4,5-c]pyridine-6-carboxylate (58 mg, 0.14 mmol), NBS (28 mg, 0.15 mmol) and benzoyl peroxide (3.4 mg, 0.014 mmol) were added to 3 mL of carbon tetrachloride. The mixture was refluxed for 16 h. After the mixture was cooled to room temperature, another 1 equiv of NBS and 0.1 equiv of benzoyl peroxide were added, and the reaction mixture was refluxed for an additional 16 h. After the mixture was cooled, 20 mL of CH2Cl2 and 1 g of silica gel were added, and the solvent was removed in vacuo. The crude was purified by flash chromatography (0-30% EtOAc/hexanes) to give 34 mg of the title compound. MS: (+) m/z 491.28, 493.25 (M+1, 79Br/81Br).
Reaction SMILES: C[O:2][C:3](=[O:18])[C@:4]([CH:16]=[CH2:17])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].CO.[OH-].[Na+].[ClH:23]>O>[ClH:23].[ClH:23].[CH:16]([C@@:4]([C:3]([OH:18])=[O:2])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5])=[CH2:17]
Reactant: C=C[C@](N)(Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C[C@](N)(Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Treatment of α-vinyltryptophan methyl ester in 1.1 methanol:water with two equivalents of sodium hydroxide, neutralization of the reaction mixture with 1 N aqueous hydrochloric acid, and purification of the crude amino acid on DOWEX 50W-X4 cation exchange resin (elution with water and then 2 N aqueous hydrochloric acid) gives α-vinyltryptophan hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][C:9]([CH2:20][CH2:21]OS(C)(=O)=O)([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1.[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][C:9]([CH2:20][CH2:21][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(CN2CC(CCOS(C)(=O)=O)(Cc3ccccc3)CC2=O)cc(OC)c1OC
Product: CCOCCn1c(N2CCCN(CCC3(Cc4ccccc4)CC(=O)N(Cc4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzyl)-3-(2-methanesulfonyloxyethyl)-3-(phenylmethyl)-5-oxopyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]4[N:33]=[CH:32][N:31](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:30]=4)[CH:27]=3)[N:22](C3CCCCO3)[N:21]=2)[CH:15]=1)=[O:13].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:30]1[C:29]([C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[C:20]3[C:16]2[CH:15]=[C:14]([C:12]([NH:11][C@H:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:10][C@H:2]3[OH:1])=[O:13])[CH:19]=[CH:18][CH:17]=2)=[N:33][CH:32]=[N:31]1
Reactant: O=C(N[C@H]1c2ccccc2C[C@H]1O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(N[C@H]1c2ccccc2C[C@H]1O)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.9 %

Procedure:
To a stirred solution of N-((1S,2R)-2-hydroxyindanyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenyl methyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.342 g, 0.448 mmol) was added 4.0M hydrochloric acid in dioxane (10.0 mL) and the mixture stirred at ambient temperature for 20 h. The mixture was cooled and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate was pipetted off. The crystals were filtered. Purification by preparative HPLC (30-80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0233 g, 12% yield). 1H NMR (CD3OD) δ 8.82 (s, 1H), 8.58 (s, 1H), 8.24 (d, 1H), 8.12 (br d, 1H), 8.00 (d, 1H), 7.01 (t, 2H), 7.37 (d, 1H), 7.30 (d, 1H), 7.24 (m, 2H), 5.63 (m, 1H), 4.74 (m, 1H), 3.26 (m, 1H), 3.05 (1H). ES-MS (m/z) 437 [M+1]+.
Reaction SMILES: C(=O)=O.CC(C)=O.[CH3:8][C:9]1[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[C:21](Cl)([Cl:23])=[O:22].Cl.CC1C=CC=CC=1NCCC(O)=O>C(Cl)Cl>[Cl:23][C:21]([N:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:10]1[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=1[CH3:8])=[O:22]
Reactant: O=C(Cl)Cl
Reactant: Cc1ccccc1NCCC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1ccccc1N(CCC(=O)O)C(=O)Cl
Temperature: 40 °C
Reaction time: 0.42 h
Yield: 97.9 %

Procedure:
In a 100 cc round-bottomed flask equipped with magnetic stirring, a thermometer, a dry ice/acetone reflux condenser, a device for introducing gas and a dropping funnel, there is introduced 3-(2-methylanilino)propionic acid (5.29 g; 29.6 mmol) and methylene chloride (30 cc). The mixture maintained under an atmosphere of argon is heated to a temperature in the region of 40° C., and phosgene (5.20 g; 52.6 mmol) is then added with stirring in the course of 25 minutes, while maintaining the temperature between 36° C. and 40° C. During the introduction of phosgene, a white precipitate of 3-(2-methylanilino)propionic acid hydrochloride forms. The reaction mixture is heated to a temperature in the region of 40° C. for a further hour. The white precipitate is then almost completely dissolved. After cooling to 20° C. and the removal of the phosgene which has not reacted, the light precipitate which remains is separated by filtration. The filtrate is concentrated to dryness. N-Chloroformyl-3-(2-methylanilino)propionic acid (7 g) is thus obtained almost pure, m.p. 112° C., the structure of which is confirmed by the infrared spectrum, mass spectrum and proton nuclear magnetic resonance spectrum. The product, after recrystallisation in a toluene/hexane mixture (70:30 by volume), melts at 113° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:4](C(OCC2C=CC=CC=2)=O)[C:3]1=[O:24]>CO.[H][H].[Pd]>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[NH:4][C:3]1=[O:24]
Reactant: [H][H]
Reactant: CN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Yield: 98.2 %

Procedure:
8.5 g of tert.-butyl (4S)-1-methyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are dissolved in 200 ml of methanol, and 0.1 g of palladium black is added thereto. The mixture is shaken at room temperature in hydrogen gas atmosphere under atmospheric pressure. After the reaction the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue obtained is washed with n-hexane. 5.0 g of tert.-butyl (4S)-1-methyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 98.2%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[Br:10]Br.S([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[Br:10][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:9])=[C:4]([Cl:8])[CH:5]=1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Oc1c(Cl)cc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mechanically stirred solution of 2,6-dichlorophenol (100 g) in acetonitrile (400 mL) was cooled to 0° C. and bromine (108 g) in acetonitrile (100 mL) was added dropwise. The red solution was stirred at 0° C. for an additional two hours and an saturated aqueous solution of sodium sulphite was added until the red color disappeared. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. Concentration of the combined organic phases gave 4-bromo-2,6-dichlorophenol as a yellow oil, which crystallized on standing. The crystalline material was washed with water and dried to give 126 g (85%) of colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:18]=[CH:17][C:13]2[N:14]=[CH:15][NH:16][C:12]=2[CH:11]=1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:18]=[CH:17][C:13]3[NH:14][CH:15]=[N:16][C:12]=3[CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nccc(Nc2ccc3[nH]cnc3c2)n1
Yield: 80 %

Procedure:
To a solution of 2,4-dichloropyrimidine (1 mmol) and 5-Aminobenzimidazole (1 mmol) in 5 ml EtOH, was added Et3N (1 mmol). The reaction mixture was refluxed for 5 hours. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography to give N-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazol-5-amine in a yield of 80%.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([CH3:31])[CH:22]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C@H:6]([C:32]([O:34]C(C)(C)C)=[O:33])[CH2:5]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>>[C:1]([N:4]1[CH2:8][C@H:7]([NH:9][S:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([CH3:31])[CH:22]=3)=[CH:17][CH:18]=2)(=[O:12])=[O:11])[C@H:6]([C:32]([OH:34])=[O:33])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)O)C1

Procedure:
According to the procedure of Example 17, Step 4, the reaction of 115 mg of tert-butyl cis-1-acetyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylate with trifluoroacetic acid provided cis-1-acetyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid in quantitative yield. MS: 484.1 (M+H)+
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[C:6]([C:15]2[CH:20]=[CH:19][C:18](F)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)=[N:7][N:8]([CH3:14])[C:9]=1[O:10][CH:11]([F:13])[F:12]>CS(C)=O>[Cl:4][C:5]1[C:6]([C:15]2[CH:20]=[CH:19][C:18]([C:1]#[N:2])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)=[N:7][N:8]([CH3:14])[C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: Cn1nc(-c2ccc(F)c([N+](=O)[O-])c2)c(Cl)c1OC(F)F
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1nc(-c2ccc(C#N)c([N+](=O)[O-])c2)c(Cl)c1OC(F)F
Temperature: 50 °C
Reaction time: 72 h

Procedure:
1.1 g (17 mmol) of potassium cyanide were added to a solution of 5.0 g (15.6 mmol) of 4-chloro-3-(4-fluoro-3-nitrophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 70 ml of dimethyl sulfoxide. The mixture was then stirred at 50° C. for 5 hours and at room temperature for 3 days. The reaction mixture was poured into ice-water and then the product was extracted with methyl tert-butyl ether. The ether phase was dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3:1). Yield: 2.7 g.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH2:7][C:8]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.O>S1(=O)(=O)CCCC1>[C:14]([C:12]1[CH:11]=[CH:10][C:9]2[C:17](=[O:19])[C:20]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:13]=1)([OH:16])=[O:15]
Reactant: O=C(O)c1ccc(C(=O)O)c(CCc2ccc(Br)cc2)c1
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=C(O)c1ccc2c(c1)CCc1ccc(Br)cc1C2=O

Procedure:
A mixture of 103.2 g. of p-bromophenylacetic acid, 77.4 g. of benzene-1,2,4-tricarboxylic anhydride and 1.5 g. of sodium acetate was heated to 275° for 2 hours. The residue was dissolved in 1600 ml of hot dimethylformamide and the solution diluted with 400 ml of water, then cooled. The solution was then filtered to afford a mixture of 3-(p-bromobenzylidene)phthalide-5- and -6-carboxylic acids. 80 g. of this mixture was refluxed for 72 hours in 160 ml of acetic anhydride and 240 ml of 57% aqueous hydriodic acid containing 35.2 g. of red phosphorus. The mixture was cooled in ice and diluted with 1000 water. The solution was filtered and the residue dissolved in 800 ml dimethylformamide and filtered. The filtrate was evaporated to yield a residue which upon recrystallization from benzene: ethanol (3:1) yielded 4-(p-bromophenethyl)benzene-1,3-dicarboxylic acid. The mother liquors were evaporated and the residue recrystallized from ethyl acetate to afford 2-(p-bromophenethyl)benzene-1,4-dicarboxylic acid. 8.5 G. of 2-(p-bromophenethyl)-benzene-1,4-dicarboxylic acid was stirred at 170° for 6 hours in a mixture of 40 ml of polyphosphonic acid and 30 ml of tetrahydrothiophene-1,1-dioxide. The mixture was then poured into water and the product filtered off and recrystallized from aqueous dimethylformamide to yield 2-carboxy-7-bromo-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene mp 252°-254°.