Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[F:17][C:18]([F:42])([F:41])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]>>[F:17][C:18]([F:41])([F:42])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=3)[CH2:14][CH2:13]2)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(C(F)(F)F)cn3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.FC(F)(F)S(O[C:15]1[C:16]2[CH2:36][N:35]([C:37](=[O:39])[CH3:38])[CH2:34][CH2:33][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[CH:24][CH:23]=2)[N:20]=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[CH:3]1([N:2]([CH3:1])[C:15]2[C:16]3[CH2:36][N:35]([C:37](=[O:39])[CH3:38])[CH2:34][CH2:33][C:17]=3[N:18]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[O:32][CH:31]=[N:30][CH:29]=4)=[CH:24][CH:23]=3)[N:20]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CNC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(C)C3CCCCC3)c2C1
Yield: 17 %

Procedure:
1-(4-(Cyclohexyl(methyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (12.6 mg, 17%) was prepared from N-methylcyclohexanamine and 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate according to the general procedure for amine substitution of tosylate on pyrimidines.
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[CH2:14][CH2:13][C:6]2=[C:7]([C:10]([OH:12])=[O:11])[S:8][CH:9]=[C:5]2[CH2:4]1)[CH3:2].[Li][CH2:18][CH2:19]CC.C(I)C>CC#N>[CH2:18]([C:9]1[S:8][C:7]([C:10]([OH:12])=[O:11])=[C:6]2[CH2:13][CH2:14][C:3]([CH2:1][CH3:2])([CH2:15][CH3:16])[CH2:4][C:5]=12)[CH3:19]
Reactant: [Li]CCCC
Reactant: CCC1(CC)CCc2c(csc2C(=O)O)C1
Solvent: CC#N
Solvent: CCI
Product: CCc1sc(C(=O)O)c2c1CC(CC)(CC)CC2

Procedure:
3,5,5-Triethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid is prepared from 5,5-diethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid by treatment with tert.-BuLi followed by ethyliodide in analogy to Example C; LC-MS: tR=1.07 min, [M+1+CH3CN]=308.14.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9].[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33](O)[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:39]2)=[CH:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([N:2]([CH3:1])[CH3:16])[CH:4]=2)[CH2:11][CH3:12])[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[CH2:39]2)=[CH:26]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1cccc(N(C)C)c1)C(=O)O
Product: CCC(Oc1cccc(N(C)C)c1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 766 mg of (2RS)-2-(3-dimethylaminophenoxy)butyric acid and 1.0 gof (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.26 g of the title compound as a pale yellow foam.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH:18]=[O:19].CC(=CC)C.Cl([O-])=[O:28].[Na+].P(=O)(O)(O)O>O1CCOCC1>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[C:18]([OH:28])=[O:19]
Reactant: [O-][Cl+][O-]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Agent: CC=C(C)C
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 46 %

Procedure:
A 200-ml three-necked flask was charged under an atmosphere of nitrogen with 8.86 g of vitamin A aldehyde (80.1% purity, 25 mmoles, ratio of 13-cis form: 92%), 50 g of 2-methyl-2-butene, 20 ml of dioxane and 10 g of a 25% aqueous sodium chlorite solution, and the mixture was mechanically stirred vigorously. Then, 32 g of an aqueous phosphoric acid solution was added dropwise thereto, while the internal temperature was maintained at 5° C., over 15 minutes. Vigorous stirring was continued at 5° C. for further 40 minutes. Confirmation of completion of the reaction and after-treatment were conducted in the same manner as in Example 1, to obtain 3.46 g of vitamin A acid with a purity of at least 99%. The yield was 46%. The vitamin A acid thus obtained had a 13-cis form ratio of 95%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:15]3=[N:14][C:13]=2[CH3:29])=[O:11])=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]1.[Cl-].[NH4+].C(OCC)(=O)C>CN1CCCC1=O>[CH:23]1([CH2:22][O:21][C:20]2[C:15]3[N:16]([C:12]([C:10]([NH:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([N:30]5[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]5)=[N:7][CH:6]=4)=[O:11])=[C:13]([CH3:29])[N:14]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)C1CCCNC1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NCc1ccc(Cl)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCCN(c2ccc(CNC(=O)c3c(C)nc4c(OCC5CCCCC5)cccn34)cn2)C1

Procedure:
To a solution of 70 mg of N-[(6-chloropyridin-3-yl)methyl]-8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridine-3-carboxamide in 1 mL of N-methyl-2-pyrrolidone was added 0.12 mL of ethyl piperidine-3-carboxylate to carry out a reaction at 240° C. for 50 minutes under microwave irradiation. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 43 mg of ethyl 1-{5-[({[8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridin-3-yl]carbonyl}amino)methyl]pyridin-2-yl}piperidine-3-carboxylate.
Reaction SMILES: CC1(C)C2C=CC(C#CC3C=CC(C(O)=O)=CC=3)=CC=2C(C(C)(C)C)=CC1.[CH3:28][C:29]1([CH3:57])[C:38]2[CH:37]=[CH:36][C:35]([C:39]#[C:40][C:41]3[CH:51]=[CH:50][C:44]([C:45]([O:47]CC)=[O:46])=[CH:43][CH:42]=3)=[CH:34][C:33]=2[C:32]([C:52]#[C:53][CH2:54][CH2:55][CH3:56])=[CH:31][CH2:30]1>>[CH3:28][C:29]1([CH3:57])[C:38]2[CH:37]=[CH:36][C:35]([C:39]#[C:40][C:41]3[CH:42]=[CH:43][C:44]([C:45]([OH:47])=[O:46])=[CH:50][CH:51]=3)=[CH:34][C:33]=2[C:32]([C:52]#[C:53][CH2:54][CH2:55][CH3:56])=[CH:31][CH2:30]1
Reactant: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Agent: CC(C)(C)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl )ethynyl]benzoic acid (Compound 80), 42.0 mg (0.106 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoate (Compound 75) was converted into the title compound (colorless solid) using 11.1 mg (0.27 mmol) of LiOH in H2O in 3 mL of THF/water (3:1, v/v, flushed with argon).
Reaction SMILES: [Si:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C(C)(C)C.[C:22]1([C@H:28]2[CH2:32][O:31][C:30](=[O:33])[NH:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([Li])CCC.O1CCNC1=O>C1COCC1>[Si:1]([O:8][CH2:9]/[CH:10]=[CH:11]/[C:12]([N:29]1[C@@H:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:32][O:31][C:30]1=[O:33])=[O:14])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: CC(C)(C)[Si](C)(C)OC/C=C/C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
To a solution of (E)-4-(tert-butyldimethylsilyloxy)but-2-enoic acid (18.0 g, 83.6 mmol) (prepared as described in Angewandte Chemie, International Edition (2002), 41(9), 1603-1607) in 400 mL of THF was added TEA (13.2 mL, 95 mmol). The mixture was chilled to −78° C. Pivaloyl chloride (10.2 mL, 83 mmol) (commercially available from Aldrich, Milwaukee, Wis.) was added. After 10 minutes, the mixture was warmed to room temperature and stirred for 45 minutes. The mixture was then chilled to −78° C. In a separate flask, (S)-4-phenyloxazolidin-2-one (12.3 g, 79 mmol) was taken up in 125 mL of THF and chilled to −78° C. n-Butyllithium (32 mL, 2.5 M in hexanes)(commercially available from Acros Organics (Order Number 30385)) was added to the (S)-4-phenyloxazolidin-2-one mixture, and the mixture was stirred for 20 minutes. The metallated oxazolidinone was then cannulated into the pivaloyl anhydride mixture. The combined mixture was then warmed to 0° C. and stirred for 1 hour. The reaction was quenched with 250 mL of aq NH4Cl and diluted with 250 mL of water. The mixture was extracted with EtOAc (2×250 mL) and the combined organic extracts were washed with brine (150 mL) and dried over MgSO4. Filtration and concentration under reduced pressure afforded a yellow solid that was recrystallized from DCM/hexanes to afford (S,E)-3-(4-(tert-butyldimethylsilyloxy)but-2-enoyl)-4-phenyloxazolidin-2-one (17.8 g, 62%) as a white solid. 1H NMR (400 MHz, CDCl3): ppm 7.46 (dt, J=2.1, 15.1 Hz, 1H), 7.31-7.20 (m, 5H), 7.02 (dt, J=3.4, 15.3 Hz, 1H), 5.40 (dd, J=3.9, 8.6 Hz, 1H), 4.61 (t, J=8.8 Hz, 1H), 4.19 (dd, J=3.9 Hz, 8.8 Hz, 1H), 0.85 (s, 9H), 0.00 (s, 6H). 2H were obscured.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:32]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][C:35]=2[F:41])=[C:31]([CH3:42])[C:30](=[O:43])[N:29]([CH3:44])[CH:28]=1)=O)#[N:21].CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Si]([N:63]=[N+:64]=[N-:65])(C)(C)C>CC#N.C(OCC)(=O)C>[Br:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:32]2[C:27]([C:25]3[N:24]([CH2:23][CH2:22][C:20]#[N:21])[N:65]=[N:64][N:63]=3)=[CH:28][N:29]([CH3:44])[C:30](=[O:43])[C:31]=2[CH3:42])=[C:35]([F:41])[CH:36]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)NCCC#N)cn(C)c1=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(Nc2ccc(Br)cc2F)c(-c2nnnn2CCC#N)cn(C)c1=O
Reaction time: 22 h
Yield: 61 %

Procedure:
PPh3 (83 mg, 0.32 mmol) was added to a stirred suspension of 4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-cyano-ethyl)-amide (51 mg, 0.12 mmol) in MeCN (1.5 mL). DIAD (0.065 mL, 0.31 mmol) and TMSN3 (0.045 mL, 0.32) were added dropwise. After 22 hours, the reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography gave clean desired product (33 mg, 61%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])C.[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:18][C:16]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([O:7][CH2:6][CH2:5][CH2:4][O:3][CH3:1])[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOCCCOc1cc(C)ccc1C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COCCCOc1cc(CBr)ccc1C(=O)OC

Procedure:
The mixture of 25.0 g of methyl 2-(3-ethoxypropoxy)-4-methylbenzoate, 18.4 g of N-bromo-succinimide, 1.65 g of 2,2′-azobis(2-methylpropionitrile) and 2.46 g of dibenzoyl peroxide in 1.2 l of carbon tetrachloride is heated to reflux with stirring and stirred over 3 hours (succinimide crystallizes out). The reaction mixture is cooled and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a slightly orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.30 (1:1 EtOAc-heptane); Rt=17.10 (II).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].N1C=CC=CC=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])([O-:20])=[O:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:24]([C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1)=[O:25])=[O:6]
Reactant: NNC(=O)c1cccc(Cl)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NNC(=O)c1cccc([N+](=O)[O-])c1)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chlorobenzohydrazide (1 equivalent) and pyridine (2 equivalents) in CH2Cl2 at 0° C. was added a CH2Cl2 solution of 3-nitrobenzoyl chloride (1 equivalents) and stirred at 0° C. for 1 h and then at room temperature for overnight. The resulting solution was concentrated and diluted with water, basified with NaHCO3, the solid was filtered, washed with water, dried and analyzed to obtain N′1-(3-chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide. 1H NMR (DMSO-d6): δ 10.99 (s, 1H), 10.79 (s, 1H), 8.73 (bs, 1H), 8.43 (bdd, 1H, J=1.2 and 8.1 Hz), 8.33 (bdd, 1J, J=8.4 Hz), 7.95 (s, 1H), 7.87 (m, 2H), 7.67 (bdd, 1H, J=1.2 and 8.1 Hz), 7.57 (t, 1H, J=7.8 Hz); LCMS: purity: 85%; MS (m/e): 320 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([N:16]([C:18]2[C:19]([Cl:38])=[C:20]([C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[C:30]([CH3:33])[CH:29]=[CH:28]3)[CH3:17])=[O:15])=[O:11])=[CH:4][CH:3]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>ClCCl>[C:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([N:16]([C:18]2[C:19]([Cl:38])=[C:20]([C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[C:30]([CH3:33])[CH:29]=[CH:28]3)[CH3:17])=[O:15])=[O:11])=[CH:4][CH:3]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CSc4ccc(N)cc4)c3Cl)c2n1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(SCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
A mixture of 8-[3-[N-[2-(4-aminophenylthio)-acetylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (56 mg) triethylamine (15 mg), and acetic anhydride (15 mg) in dichloromethane (2 ml) was stirred for 4 hours at ambient temperature. The resulting precipitates were collected by filtration to give 8-[3-[N-[2-(4-acetamidophenylthio)acetylglycyl]-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (30 mg) as a colorless crystal.
Reaction SMILES: N[C@H](C(O)=O)CC(O)=O.N[C@H](C([O-])=O)CC([O-])=O.[C:19]([NH:26][C@H:27]([C:32]([O-:34])=[O:33])[CH2:28][C:29]([O-:31])=O)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(OC(=O)C)(=O)C>>[C:22]([O:21][C:19]([NH:26][C@@H:27]1[C:32](=[O:33])[O:34][C:29](=[O:31])[CH2:28]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)[O-])C(=O)[O-]
Agent: N[C@@H](CC(=O)O)C(=O)O
Agent: N[C@@H](CC(=O)[O-])C(=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)OC1=O

Procedure:
Due to its low cost, L-aspartic acid appears to be the most attractive starting material for the preparation of (S)-3-amino-1-substituted-pyrrolidines. The literature method from L-aspartate (D. T. Witiak, loc. cit.) involves treatment of N-boc-L-aspartate with acetic anhydride to give (S)-3-(tert-butoxycarbonylamino)succinic anhydride followed by addition of a primary amine and ring closure with heat to give the succinimide, (S)-3-(tert-butoxycarbonylamino)-1-substituted pyrrolidine-2,5-dione. The latter is then reduced and deblocked to give the 1-substituted-3-aminopyrrolidine in low overall yield. From our experience with this method some racemization takes place when the blocking group is p-toluenesulfonyl(tosyl) and the primary amine is benzylamine.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]3=[N:14][C:15]([NH:18][C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[N:16][CH:17]=[C:12]3[CH:11]=[N:10]2)[CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)Cl>[CH3:24][N:22]1[CH:23]=[C:19]([NH:18][C:15]2[N:14]=[C:13]3[N:9]([CH2:8][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[N:7]=4)[N:10]=[CH:11][C:12]3=[CH:17][N:16]=2)[CH:20]=[N:21]1
Reactant: C1COCCN1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(F)n4)c3n2)cn1
Solvent: ClCCl
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(N5CCOCC5)n4)c3n2)cn1
Temperature: 180 °C
Yield: 64 %

Procedure:
1-((6-fluoropyridin-2-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Example 170) (27 mg, 0.08 mmol) was dissolved in morpholine (0.6 ml) in a microwave tube under Nitrogen which was sealed and heated at 180° C. for 1 h. The mixture was diluted with DCM, washed with water and the water re-extracted with DCM. The combined organics were dried over Na2SO4, filtered and the solvent evaporated to give the title compound as a yellowish solid (20 mg, 64% yield). 1H NMR (d6-DMSO) δ 9.78 (br s, 1H), 8.91 (s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.52 (s, 1H), 7.46 (t, 1H), 6.68 (d, 1H), 6.28 (br s, 1H), 5.46 (s, 2H), 3.78 (s, 3H), 3.62 (t, 4H), 3.35 (t, 4H); LC-MS method B, (ES+) 392.0, RT=6.84 min.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:10][C:9]=2[N+:16]([O-:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1cc(CN2CCCCC2)ccc1NC1CCCCC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyclohexylamino-3-nitrobenzaldehyde (10.3 g, 41.3 mmol) in dichloroethane (50 mL) was added piperidine (4.10 g, 48.2 mmol) followed by acetic acid (0.20 mL, cat.). The reaction mixture was heated to 60° C. and stirred for 1 hr, then cooled to room temperature and sodium triacetoxyborohydride (10.5 g, 49.5 mmol) was added in a single portion. After stirring for 18 hr at room temperature, the reaction was quenched by the addition of sodium bicarbonate (sat., aq., 100 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were then evaporated to afford crude N-cyclohexyl-2-nitro-4-(1-piperidinylmethyl) aniline as a yellow oil (15.4 g crude yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[CH:31]1([NH:34][C:14]([C:7]2([CH3:17])[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=3[CH3:18])[O:8]2)=[O:16])[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NC1CC1)O2
Yield: 39.2 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 357 mg CDI (2.00 mmol) and 126 mg cyclopropylamine (2.2 mmol) produced 227 mg of N-cyclopropyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([OH:19])=O)[C:10](=[O:20])[CH:9]=2)[CH:7]=1.[NH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:26][CH:25]=3)=[O:19])[C:10](=[O:20])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(CC(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cn(CC(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
159 mg (499 μmol) of [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetic acid, 116 mg (599 μmol) of tert-butyl 4-aminobenzoate, 228 mg (599 μmol) of HATU and 261 μl (1.50 mmol) of N,N-diisopropylethylamine in 8 ml of dimethylformamide were reacted according to General Method 5A. The solvent was removed and the residue was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 54.5 mg (22% of theory)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6][C:7]1[NH:11][C:10]2[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[N:8]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][S:6]([C:7]1[NH:8][C:9]2[CH2:15][CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=1)=[O:28]
Reactant: CNc1ccccc1CSc1nc2c([nH]1)CCCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CNc1ccccc1CS(=O)c1nc2c([nH]1)CCCC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
To a solution of 1.20 g (4 mmol) of 2-(2-methylaminobenzylthio)-4,5,6,7-tetrahydro-1H-benzimidazole in chloroform was added under chilling with ice 0.85 g (4 mmol) of 80% m-chloroperbenzoic acid for 20 min. The 30 mixture was then stirred for 15 min. The chloroform portion was washed with a saturated aqueous NaHCO3 solution. The chloroform portion was then extracted with two portions of diluted aqueous NaOH solution. The aqueous extracts were combined, and an excess amount of aqueous NH4Cl was added to the combined extracts to precipitate a crystalline product. The crystalline products were collected by filtration and sufficiently washed. The thus obtained crude crystalline product was recrystallized from dichloromethane/hexane to give 0.32 g of the desired compound as a white crystalline product, yield 25%.