Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:13])[CH:2]([CH3:4])[CH3:3].[CH2:42]([O:49][C:50]([NH:52][C@H:53](C(O)=O)[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:41][C:38]1[CH:39]=[CH:40][C:35]([S:32]([N:5]([C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@@H:53]([NH:52][C:50]([O:49][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:51])[CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[O:13])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:33])=[O:34])=[CH:36][CH:37]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using commercially available Nα-benzyloxycarbonyl-L-phenylalanine (300 mg, 1.2 mmol). The final product was purified by preparative HPLC to yield 33 mg (37%) of the desired material.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]([CH3:29])([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[NH2:23]>>[CH3:21][C:22]([NH:23][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH3:29]
Reactant: O=C(O)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(C2CCOCC2)c(OCC2CC2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9 f) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (LC/MS): 402.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][C:16]([N:18]([C:20]2[C:21]([Cl:48])=[C:22]([C:44]([Cl:47])=[CH:45][CH:46]=2)[CH2:23][O:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[C:32]([CH3:35])[CH:31]=[C:30]3[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[CH3:19])=[O:17])=[O:13])=[CH:6][CH:5]=1)(O)=[O:2].Cl.CN.Cl.[CH2:53]([N:55]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:48][C:21]1[C:20]([N:18]([CH3:19])[C:16](=[O:17])[CH2:15][NH:14][C:12](=[O:13])/[CH:11]=[CH:10]/[C:7]2[CH:8]=[N:9][C:4]([C:1](=[O:2])[NH:55][CH3:53])=[CH:5][CH:6]=2)=[CH:46][CH:45]=[C:44]([Cl:47])[C:22]=1[CH2:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[C:32]([CH3:35])[CH:31]=[C:30]2[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(OCc5ccccn5)cc(C)nc34)c2Cl)cn1
Reaction time: 24 h
Yield: 19.6 %

Procedure:
To a solution of 8-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (25 mg) and methylamine hydrochloride (3 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7 mg) and 1-hydroxybenzotriazole (7 mg) at ambient temperature, and the mixture was allowed to stand for 1 day at ambient temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(methylcarbamoyl)pyridin-3-yl]acryloylglycyl]amino]-benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (5 mg) as an oil.
Reaction SMILES: C(C1N=[C:7]([N:22]2C[CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2N=NN(CC3C=CC=CC=3Cl)[C:9]=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].COC[C@H]1CCCN1>>[C:28]([C:32]1[N:33]=[C:34]([N:22]2[CH2:7][CH2:8][CH2:9][C@@H:23]2[CH2:24][O:25][CH3:26])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: COC[C@H]1CCCN1
Product: COC[C@H]1CCCN1c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-2-(methoxymethyl)pyrrolidine and isolated as colorless gum (12.4 mg, 64%). MS(m/e): 415.4 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:17])([CH3:16])[CH3:15])[CH2:10][CH2:9]1.[H-].[Na+].[CH3:20]I.O>C1COCC1>[CH3:20][O:17][C:14]([C@H:11]1[CH2:12][CH2:13][C@H:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:9][CH2:10]1)([CH3:15])[CH3:16]
Reactant: CC(C)(O)[C@H]1CC[C@H](OC2CCCCO2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(C)(C)[C@H]1CC[C@H](OC2CCCCO2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((trans)-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl)propan-2-ol (1.56 g, 6.5 mmol) in THF (10 mL) was added NaH (300 mg, 13 mmol, 2.0 eq) slowly at r.t. and then CH3I (1.96 g, 13 mmol, 2.0 eq) was added in one portion. The mixture was stirred at 50° C. for 2 h, Water (10 mL) was added and the mixture was extracted with EA (30 mL×3), dried and concentrated to give the title compound as a colorless oil (1.2 g, yield: 72%). 1H NMR (400 MHz, CDCl3) δ: 4.64 (t, 1H), 3.93-3.89 (m, 2H), 3.51-3.47 (m, 1H), 3.17 (s, 3H), 1.97-1.85 (m, 3H), 1.70-1.67 (m, 1H), 1.58-1.43 (m, 9H), 1.34-1.27 (m, 2H), 1.09 (d, 6H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.C(N1CCOCC1)C.[NH2:56][CH2:57][C@H:58]([OH:61])[CH2:59][OH:60].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:56][CH2:57][C@H:58]([OH:61])[CH2:59][OH:60])=[O:19])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: NC[C@H](O)CO
Agent: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NC[C@H](O)CO)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 29 %

Procedure:
A solution of 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 4) (90 mg, 0.211 mmol) in DMF (2 mL) was treated with EDC (48.5 mg, 0.253 mmol), HOBT hydrochloride (38.8 mg, 0.253 mmol) and N-ethylmorpholine (0.080 mL, 0.633 mmol) and after 3 min with (S)-3-aminopropane-1,2-diol (38.5 mg, 0.422 mmol). The resulting mixture was stirred at room temperature for 5 h then EDC (48.5 mg, 0.253 mmol), N-ethyl morpholine (0.080 mL, 0.633 mmol), HOBT (38.8 mg, 0.253 mmol) and further (S)-3-aminopropane-1,2-diol (38.5 mg, 0.422 mmol) were added and the corresponding mixture was stirred for 16 h then concentrated in vacuo. The residue was partitioned between water and EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 (×3), then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP to give 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N—((S)-2,3-dihydroxypropyl)benzamide (30 mg, 29%) as a white solid. LCMS (HpH, 2 min), Rt=0.75 min, MH+=500.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[CH3:12][C:13]1[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][C:14]=1[N+:1]([O-:4])=[O:2]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: Cc1sc(C(=O)O)cc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
Under N2, fuming nitric acid (4.7 mL, 112.0 mmol) was added slowly over 10 min to acetic anhydride (16.6 mL, 175.6 mmol) cooled in a dry ice/acetone bath to −78° C. 5-methyl-2-thiophene carboxylic acid (5.0 g, 35.2 mmol) was added in 1 g portions over 10 min to the solution. The reaction was kept at −20° C. for 1 h before quenching over ice. The yellow solid was filtered off and washed with water (200 mL). The crude product was recrystallized from 95% EtOH to give 5-methyl-4-nitro-2-thiophene carboxylic acid as a pale yellow solid (4.6 g, 70%). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.13 (s, 1H) 2.82 (s, 3H).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[N:20]=2)[CH2:6][C@H:5]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N+:2]=[N-:3].C.[CH:44]#[C:45][CH3:46].C(N(CC)CC)C>O1CCOCC1.[Cu]>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[C:21]1[N:20]=[C:19]([C:18]([NH:17][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:11]=2[N:7]2[CH2:8][C@H:9]([CH3:10])[C@H:4]([N:1]3[CH:44]=[C:45]([CH3:46])[N:3]=[N:2]3)[C@H:5]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:6]2)=[O:34])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Reactant: C#CC
Agent: [Cu]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cn([C@H]2[C@@H](C)CN(c3ccncc3NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)C[C@H]2NC(=O)OC(C)(C)C)nn1
Temperature: 60 °C
Yield: 95 %

Procedure:
In a high pressure vial was added tert-butyl (3R,4S,5S)-4-azido-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate (1.0 equiv.), copper in charcoal (0.2 equiv.), prop-1-yne (10.0 equiv.) and triethylamine (1.5 equiv.), in dioxane (0.15 M) to give a black suspension. The pressure tube was sealed and the mixture was stirred with heating to 60° C. for 48 hrs. The reaction was cooled to RT, filtered through celite, concentrated to yield tert-butyl (3R,4S,5S)-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methyl-4-(4-methyl-1H-1,2,3-triazol-1-yl)piperidin-3-ylcarbamate in 95% yield. LC/MS (m/z)=623.2 (MH+), Rt=0.87 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([C:8]2([OH:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:30][C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=2)=[C:6]([C:8]2([OH:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2C1(O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1Nc2cc(C(F)(F)F)ccc2C1(O)c1cc(Cl)ccc1OCc1ccc(C(F)(F)F)cc1
Temperature: 77.5 °C
Yield: 59.9 %

Procedure:
To a solution of (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indole-2-one (Preparation 5, 80 mg, 0.233 mmol) in 2-butanone (3mL), was added 4-(trifluoromethyl) benzyl bromide (61 mg, 0.256 mmol), K2CO3 (32 mg, 0.233 mmol) and a catalytic amount of KI. The reaction mixture was heated at 75-80° C. for 2 days. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The resulting crude product was purified by preparative HPLC to afford the title compound (70 mg, 60% yield); MS m/e 500 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:26])[N:10]([CH3:11])[CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: C1CCNCC1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COCCCCN2CCCCC2)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the method described in example 12.1, trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was reacted with piperidine in N,N-dimethylacetamide at 50° C. for 2 hours to yield trans-methyl-[4-(4-piperidin-1-yl-butoxymethyl)-cyclohexylmethyl]-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 451 (MH+, 1Cl).
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[C:7]1[O:13][C@H:12]([C@H:14]([CH2:16][OH:17])[OH:15])[C:10]([OH:11])=[C:8]1[OH:9].[N:18]1[N:19]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[OH:36])[C:30](O)=[O:31])[N:20]=[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=12.OS(O)(=O)=O.O=S(=O)=O.[Cl-].[Na+]>>[N:18]1[N:19]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[OH:36])[C:30]([O:17][CH2:16][C@H:14]([C@@H:12]2[C:10]([OH:11])=[C:8]([OH:9])[C:7](=[O:6])[O:13]2)[OH:15])=[O:31])[N:20]=[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=12
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: O=C(O)c1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Cl-]
Product: O=C1O[C@H]([C@H](O)COC(=O)c2ccc(O)c(-n3nc4ccccc4n3)c2)C(O)=C1O
Temperature: 0 °C

Procedure:
265 ml of conc. sulfuric acid are initially introduced in an argon-flushed 3-necked flask and cooled to 0° C. 124.2 g (0.705 mol, 3 eq.) of ascorbic acid and subsequently 60 g of 3-benzotriazol-2-yl-4-hydroxybenzoic acid (0.235 mol, 1 eq.) are added in portions. 73.7 ml of oleum (sulfuric acid containing 65% of SO3) are then added dropwise. After a reaction time of 5 hrs. at 45° C., the reaction solution is poured onto 1000 g of ice, saturated with 200 g of sodium chloride and extracted 3× with 1000 ml of ethyl methyl ketone. The combined org. phases are extracted with 500 ml of sat. NaCl solution, dried over sodium sulfate, and the solvent is removed in vacuo. Crystallisation from ethyl acetate gives the product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])(=O)C.[Na+]>C(O)C.C(OCC)C>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:14]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CNc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aniline (0.096 mole), ethyl bromoacetate (0.096 mole) and sodium acetate (0.096 mole) in ethanol (150 ml) were refluxed for four hours and stirred at room temperature for 18 hours. The ethanol was removed by a rotary evaporator to give an oil. The oil was dissolved in ethyl ether (200 ml), filtered and the solvent removed by a rotary evaporator. The dark oily residue crystallized from cold hexane. Structural assignment was supported by NMR and the compound is used as is to prepare title compound of Example 1.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=2)[CH:5]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]2([CH3:36])[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH2:19][C@@H:18]1[CH3:37].I[CH2:39][CH3:40].O>CN(C=O)C>[CH2:39]([O:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:10]=2)[CH:5]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]2([CH3:36])[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)[CH2:19][C@@H:18]1[CH3:37])[CH3:40]
Reactant: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1c2ccc(C(F)(F)F)cc2CC1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC1Cc2cc(C(F)(F)F)ccc2C1N1CCN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
Sodium hydride (5.225 g, 0.1306 mol) was mixed with dry DMF (150 mL) at 0° C. A solution of t-butyl 4-{(3S)-4-[2-hydroxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidine-1-carboxylate (50.0 g, 0.1005 mol) in DMF (100 mL) was added dropwise at 0° C over 20 min. After the addition, the mixture was stirred for another 20 min before iodoethane (12.06 mL, 0.1507 mol) was added at one portion. After being stirred for 1 h, the reaction content was carefully poured into 500 mL icy water. The mixture was extracted with methylene chloride (500 mL×3). The combined organic layer was washed with brine, and dried over magnesium sulfate. After the removal of the solvent, the residue was dissolved in methylene chloride, and passed through a silica plug with ethyl acetate/hexane/triethylamine 50:50:1 (the plug was presaturated with the same solvent system). After removal of the solvent, 48.4 g (91.6%) of product was obtained as a sticky solid, MS (EI) 526.2 (M+1).
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:55]([OH:56])[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][O:47]CC7C=CC=CC=7)[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:57]([CH3:59])[CH3:58])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[OH:47][CH2:46][CH2:45][CH2:44][O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:57]([CH3:58])[CH3:59])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:55]([OH:56])[CH:41]1[O:40]3)[O:36]2
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(OCCCOCc6ccccc6)C5O2)C4O)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(OCCCO)C5O2)C4O)C13C(=O)O
Yield: 90 %

Procedure:
38.3 mg of compound (73) was dissolved in 0.9 ml of ethyl acetate and stirred together with a catalytic amount of 10% palladium-carbon under a hydrogen atmosphere at room temperature for 2.5 hours. The reaction solution was filtered and concentrated in vacuo. The reaction product was dissolved in 10 ml of methanol and washed with 15 ml of n-hexane four times, and the lower layer was concentrated in vacuo to give 23.5 mg of compound (74) as a colorless solid.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].O1CCOCC1.[OH-].[Na+].Cl[CH:24]([F:26])[F:25]>C(Cl)Cl.CCCCCC.O>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:24]([F:26])[F:25])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2]
Reactant: FC(F)Cl
Reactant: CC(C)C(C(=O)O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)C(C(=O)O)c1ccc(OC(F)F)cc1
Temperature: 80 °C
Yield: 43 %

Procedure:
Into an 80° C. magnetically-stirred mixture of 10.00 g (0.0515 mol) of α-isopropyl-4-hydroxyphenylacetic acid, 65 ml of dioxane, 19.08 g (0.464 mol) of sodium hydroxide, and 30 ml of water is bubbled 46 g (0.532 mol) of chlorodifluoromethane over a period of 4 hours. The reaction mixture is poured into 250 ml of ice water and the resulting mixture is washed with ether, acidified with concentrated hydrochloric acid to pH 3, and then extracted with 200 ml of ether. The ether solution is washed once with 100 ml of water, dried with sodium sulfate, filtered, and then evaporated to give a white paste. A mixture of hexane and methylene chloride is added and the resulting mixture is filtered to remove the solid which is the starting material. The filtrate is evaporated to give 5.41 g of a clear brown oil. It is estimated that the product thus obtained is at least 85% pure as determined by NMR. NMR (CDCl3 -d5 pyridine), δ7.43 (d, J=8.2 Hz, 2H), δ7.08 (d, J=8.2 Hz, 2H), δ6.57 (t, J=74.3 Hz, 1H), δ3.63 (s, imp.), δ3.25 (d, J=10 Hz, 1H), δ2.37 (m, 1H, δ1.19 (d, J=6.5 Hz, 3H, δ0.78 (d, J=6.5 Hz, 3H), δ13.82 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26].[N:27]1([CH2:32][C@@H:33]2[CH2:37][CH2:36][CH2:35][NH:34]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:34]3[CH2:35][CH2:36][CH2:37][C@H:33]3[CH2:32][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:14])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(F)cccc1F
Reactant: C1CN[C@H](CN2CCCC2)C1
Product: Nc1ncc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1OCc1c(F)cccc1F

Procedure:
{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone was prepared from 4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid and (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]=1)[NH2:7].[F:9][C:10]([F:15])([F:14])[C:11](O)=O>>[CH2:6]([N:7]1[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:8][C:6]=2[N:7]=[C:11]1[C:10]([F:15])([F:14])[F:9])[C:5]#[CH:4]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cccc(F)c1
Product: C#CCn1c(C(F)(F)F)nc2cc(F)ccc21
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a stirred solution of 5.0 grams (0.030 mole) of 2-propyn-1-ylamino)-5-fluoroaniline in 70 mL of trifluoroacetic acid was heated at reflux for 1.5 hours. The reaction mixture was then cooled to ambient temperature and poured into ice water. The mixture was extracted thoroughly with portions of diethyl ether. The combined extracts were washed with an aqueous solution saturated with sodium bicarbonate and then dried with magnesium sulfate. The mixture was filtered, and the filtrate concentrated under reduced pressure to a residual oil. The oil was triturated with cold water, and the resultant solid was collected by filtration. The solid was dried, yielding 5.0 grams of 1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluorobenzimidazole. The NMR spectrum was consistent with the proposed structure. The reaction was repeated.