Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:13][C:12]2[C@@H:11]3[CH2:14][C@@H:10]3[CH2:9][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Li+].CO>C1COCC1>[CH2:14]1[C@@H:10]2[CH2:9][C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:13][C:12]=3[C@H:11]12
Reactant: CCOC(=O)c1cc2c([nH]1)[C@@H]1C[C@@H]1C2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)[C@@H]1C[C@@H]1C2

Procedure:
The title compound was synthesized from (1aR,5aR)-1a,2,5,5a-tetrahydro-1H-2-aza-cyclopropa[α]pentalene-3-carboxylic acid ethyl ester (115 mg, 0.6 mmol) and lithium hydroxide (252 mg, 6.0 mmol in 5 mL water) according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (10 mL) was used. The resulting product was purified by chromatography eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. 27 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.31-0.39 (m, 1H), 1.06-1.16 (m, 1H), 2.04-2.19 (m, 2H), 2.63 (d, J=15.67 Hz, 1H), 2.84 (dd, J=15.62, 6.35 Hz, 1H), 6.73 (s, 1H), 8.97 (br. s, 1H). LCMS m/e 164 (M+H). Purity>85% (HPLC).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([CH:17]=[CH2:18])[CH2:13][CH2:12]2)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[CH2:19]([SiH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20].[NH4+].[Cl-]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([CH2:17][CH2:18][Si:21]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:19][CH3:20])[CH2:13][CH2:12]2)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CC[SiH](CC)CC
Reactant: C=C[C@H]1CC[C@@H](Nc2ncnc(CC)c2Cl)CC1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [H+]
Product: CCc1ncnc(N[C@H]2CC[C@@H](CC[Si](CC)(CC)CC)CC2)c1Cl

Procedure:
2.0 g (7.3 mmol) of 5-chloro-4-(cis-4-ethenylcyclohexylamino)-6-ethylpyrimidine (Example 12) and 1.22 g (10.5 mmol) of triethylsilane were heated under reflux with a spatula tip of hexachloroplatinic acid. After hydrolysis with dilute NH4Cl solution, the mixture was subjected to extraction with ether and purified by column chromatography (silica gel, eluent system petroleum ether/ethyl acetate 9:1). 0.72 g (1.9 mmol=25%) was obtained of the silane (colorless oil, nD23 =1.5206).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[C:20]([CH3:22])[C:19]3[C:14](=[CH:15][C:16]([N:23]([S:30]([C:33]4[CH:34]=[CH:35][CH:36]=[C:37]5[C:42]=4[N:41]=[CH:40][CH:39]=[CH:38]5)(=[O:32])=[O:31])[CH2:24][C:25]([O:27]CC)=[O:26])=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[C:20]([CH3:22])[C:19]3[C:14](=[CH:15][C:16]([N:23]([S:30]([C:33]4[CH:34]=[CH:35][CH:36]=[C:37]5[C:42]=4[N:41]=[CH:40][CH:39]=[CH:38]5)(=[O:32])=[O:31])[CH2:24][C:25]([OH:27])=[O:26])=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)CN(c1ccc2c(C)cc(COc3ccc(C(=N)N)cc3)nc2c1)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(COc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3cccc4cccnc34)ccc12

Procedure:
Prepared analogously to Example 3 from 2-[(4-amidinophenyl)-oxymethyl]-4-methyl-7-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-quinoline and sodium hydroxide solution.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[F:1][C:2]1[CH:9]=[C:8]([N:18]2[CH2:19][CH2:20][C@H:16]([C:13]([OH:12])([CH3:15])[CH3:14])[C@@H:17]2[CH3:21])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1cc(F)c(C#N)c(F)c1

Procedure:
Using 2,4,6-trifluorobenzonitrile (786 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.04 g) and lithium carbonate (784 mg), the title compound was obtained as a colorless solid (yield: 538 mg) by an operation similar to that in Example 3.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C@@H:5]([NH:19][CH2:20][P:21]([O:25][CH3:26])([O:23][CH3:24])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[C:10]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([NH:19][CH2:20][P:21]([O:25][CH3:26])([O:23][CH3:24])=[O:22])[CH2:4][C:3]([OH:27])=[O:2])=[CH:12][CH:11]=1
Reactant: COC(=O)C[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COP(=O)(CN[C@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1)OC
Reaction time: 1 h

Procedure:
To a solution of (S)-4-(biphenyl-4-yl)-3-[(dimethylphosphonomethyl)-amino]-butyric acid methyl ester (851 mg, 2.26 mmol) in methanol (2 mL) is added 2N sodium hydroxide (1.5 mL, 3 mmol). After 1 hour of stirring, methanol is removed under vacuum and water (5 mL) is added to the residue. The aqueous layer is washed with ethyl acetate (10 mL), then acidified with 1N hydrochloric acid (4 mL). The residue is extracted with ethyl acetate (2×10 mL) and methylene chloride (10 mL). The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield (S)-4-(biphenyl-4-yl)-3-[(dimethylphosphonomethyl)-amino]-butyric acid as a gummy solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[CH2:10][C:11]1([C:16]([NH:18][CH:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[CH2:10][C:11]1([C:16]([NH:18][CH:19]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:33][CH:34]=2)[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)C1(CC(=O)OCc2ccccc2)CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)C1(CC(=O)OCc2ccccc2)CCCC1
Reaction time: 1 h
Yield: 114.8 %

Procedure:
To a solution of tert-butyl 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-4-(biphenyl-4-yl)butanoate (38 mg, 0.068 mmol) in DCM (0.7 ml), TFA (0.263 ml, 3.42 mmol) was added. After stirred for 1 hour, the reaction mixture was concentrated to give 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-4-(biphenyl-4-yl)butanoic acid (39 mg); Retention time=1.73 minutes (condition B); MS (m+1)=500.4;
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([C@H:11]([CH3:19])[CH2:12][CH2:13][C@H:14]([CH3:18])[CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:8][C@H:7]1[C@@H:6]([OH:20])[CH2:5][CH2:4][CH2:3]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][C@@:2]12[C@@H:10]([C@H:11]([CH3:19])[CH2:12][CH2:13][C@H:14]([CH3:18])[CH:15]([CH3:16])[CH3:17])[CH2:9][CH2:8][C@H:7]1[C:6](=[O:20])[CH2:5][CH2:4][CH2:3]2
Reactant: CC(C)[C@@H](C)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)[C@@H](C)CC[C@@H](C)[C@H]1CC[C@H]2C(=O)CCC[C@]12C
Temperature: 0 °C

Procedure:
The compound of Example 7B (66 mg, 0.25 mmol) was dissolved in 5 mL of dichloromethane and cooled to 0° C.; 370 mg of pyridinium dichromate and 2 mg of pyridinium p-toluenesulfonate were added, and the resultant mixture was shaken at ambient temperature for 4 hours. The reaction was filtered first through a pad of diatomaceous earth, then through a pad of silica gel, with ethyl acetate washes. The combined filtrate was concentrated and purified by chromatography on an Analogix Intelliflash 280™, eluting with 10% ethyl acetate in hexanes to provide the titled compound, 56 mg.
Reaction SMILES: CN(C=O)C.[N:6]1([CH2:10][C@@H:11]2[CH2:14][C@H:13]([N:15]3[C:19]4[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=4[C:17](I)=[CH:16]3)[CH2:12]2)[CH2:9][CH2:8][CH2:7]1.[C:26]1([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:38]=3)[N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:6]1([CH2:10][C@@H:11]2[CH2:14][C@H:13]([N:15]3[C:19]4[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=4[C:17]([C:36]4[CH:35]=[C:34]5[C:39]([CH:40]=[CH:41][C:32]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:33]5)=[CH:38][CH:37]=4)=[CH:16]3)[CH2:12]2)[CH2:9][CH2:8][CH2:7]1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](CN2CCC2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@@H](CN2CCC2)C1
Temperature: 80 °C

Procedure:
To the DMF solution from the preparation of cis-7-(3-azetidin-1-ylmethylcyclobutyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine were added 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (40 mg, 0.12 mmol), Na2CO3 (27 mg, 0.25 mmol), Pd(PPh3)4 (7 mg, 0.006 mmol), and water (0.6 mL). The solution was purged with nitrogen for 10 min and heated to 80° C. for 16 h. To the cooled reaction solution was added sat. Na2CO3 solution (10 mL), the mixture was extracted with EtOAc (3×20 mL), the combined organic layers were washed with water (3×15 mL) and brine, dried over MgSO4, filtered, and concentrated to give a brown oil. Purification by HPLC gave the title compound as brown oil. 1H NMR (CDCl3, 400 MHz): δ=2.06-2.26 (m, 5H), 2.56-2.57 (d, 2H, J=6.2), 2.71-2.77 (m, 2H), 3.21-3.24 (m, 4H), 5.17 (brs, 2H), 5.19-5.26 (m, 1H), 7.31 (s, 1H), 7.46-7.56 (m, 3H), 7.69-7.71 (dd, 1H, J=1.6 & 8.4 Hz), 7.90-7.94 (m, 2H), 8.18-8.20 (m, 2H), 8.26-8.29 (m, 2H), 8.35 (s, 1H). MS (ES+): 461.2 [MH+]. HPLC: tR=2.0 min (polar—5 min).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Sc2ccc(O)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(S[C@@H]2CCNC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.7 %

Procedure:
(R)-3-(4-Hydroxy-phenylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.0 g, 10.2 mmol) in CH2Cl2 (36 ml) was treated with trifluoroacetic acid (7.8 ml, 0.1 mol). After 1 hour stirring at room temperature, the reaction mixture was concentrated to provide (R)-4-(pyrrolidin-3-yl-sulfanyl)-phenol trifluoroacetic acid (3.46 g) as an orange oil, MS: m/e=196.2 (M+H+) and [α]D20=+25.060 ° (c=1.2, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=1)[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7].C(OC(N1CCC(NC(=O)C2C=C(OCC3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)C=C(OC)C=2)CC1)=O)(C)(C)C.C(OC(N1CCC(NC(=O)C2C=C(OCC3N=NN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=3)C=C(OC)C=2)CC1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH2:132]([O:134][C:135]1[CH:136]=[C:137]([CH:140]=[C:141]([O:144][CH2:145][CH3:146])[C:142]=1[F:143])[CH:138]=O)[CH3:133].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>ClCCl.C(O)C.C(O)(=O)C>[CH2:132]([O:134][C:135]1[CH:136]=[C:137]([CH:140]=[C:141]([O:144][CH2:145][CH3:146])[C:142]=1[F:143])[CH2:138][N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[C:5]2[CH:15]=[C:16]([O:18][CH2:19][C:20]3[NH:21][N:22]=[N:23][N:24]=3)[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13]1)[CH3:133]
Reactant: COc1cc(OCc2nnn[nH]2)cc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Agent: COc1cc(OCc2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: COc1cc(OCc2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCc4nnn[nH]4)c3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 50k), 3-methoxy-N-piperidin-4-yl-5-(1H-tetrazol-5-ylmethoxy)-benzamide [prepared from 4-[3-methoxy-5-(1-trityl-1H-tetrazol-5-ylmethoxy)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester and/or 4-[3-methoxy-5-(2-trityl-2H-tetrazol-5-ylmethoxy)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester by reaction with trifluoroacetic acid in dichloromethane in analogy to the procedure described in example 50i)] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 529.2 (MH+).
Reaction SMILES: FC1C2C(C(=O)NC)=C(C3C=CC(F)=CC=3)OC=2C=CC=1C1C=C(C=CC=1C)C(O)=O.[NH:32]1[C:40]2[C:35](=[N:36][C:37]([C:41]3([NH2:44])CC3)=[CH:38][CH:39]=2)[CH:34]=[CH:33]1>>[NH:32]1[C:40]2[C:35](=[N:36][C:37]([C:41]#[N:44])=[CH:38][CH:39]=2)[CH:34]=[CH:33]1
Reactant: NC1(c2ccc3[nH]ccc3n2)CC1
Agent: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Product: N#Cc1ccc2[nH]ccc2n1

Procedure:
This example was prepared from the coupling of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid with 1-(1H-pyrrolo[3,2-b]pyridin-5-yl)cyclopropanamine (obtained from 1H-pyrrolo[3,2-b]pyridine-5-carbonitrile by the reaction using Ti(OiPr)4/EtMgBr/BF3OEt2). Purification was performed by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=10, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Sunfire Prep C18 19×100 5 um, Fraction Collection: 7.86-8.38 min. (UV detection at 220 nm). The material obtained was further purified by preparative TLC (500 um×20×20 cm plate, 5% MeOH/CH2Cl2). Analytical TLC Rf=0.30 (5% MeOH/CH2Cl2). 1H NMR (500 MHz, CD3OD) δ 7.96 (m, 2H), 7.90 (dd, J=7.93, 2.14, 1H), 7.83 (d, J=1.83, 1H), 7.72 (dd, J=8.55, 0.92, 1H), 7.54 (d, J=8.55, 1H), 7.51 (d, J=3.36, 1H), 7.48 (d, J=7.93, 1H), 7.34-7.27 (overlapping m, 4H), 6.55 (dd, J=3.36, 0.92, 1H), 2.96 (s, 3H), 2.29 (s, 3H), 1.69 (m, 2H), 1.38 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=577.19, HPLC Rt=1.433 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=20, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=7.74 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=8.42 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=9.87 min. tert-butyl 1-(1,6-naphthyridin-2-yl)cyclopropylcarbamate was synthesized in a similar fashion then converted to 1-(1,6-naphthyridin-2-yl)cyclopropanamine using the following approach.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:13]=[CH:12][C:6]([C:7](=[NH:11])OCC)=[CH:5][CH:4]=1.[CH:14]([NH:16][NH2:17])=O.C(N(CC)CC)C>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[NH:11][CH:14]=[N:16][N:17]=2)=[CH:12][CH:13]=1
Reactant: NNC=O
Reactant: CCOC(=N)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Brc1ccc(-c2nnc[nH]2)cc1
Temperature: 85 °C
Yield: 48.3 %

Procedure:
Ethyl 4-bromobenzimidate hydrochloride (35.6 g, 135 mmol), formic hydrazide (16.16 g, 269 mmol) and triethylamine (75 mL, 538 mmol) were combined in a screw capped flask and heated to 85° C. for 16 h. The solution was condensed under reduced pressure to afford a solid, which was partitioned between water and ethyl acetate (3×), dried over magnesium sulfate and solvent removed under reduced pressure. The resulting solid was sonicated with 20% ethyl acetate in hexanes, filtered and dried to afford the title compound (14.6 g, 65.2 mmol, 48% yield). MS (ESI) m/z 224.1 [M]+, 226.1 [M+2]+.
Reaction SMILES: ClP(C(C)(C)C)C(C)(C)C.Br[C:12]1[C:17]2=[CH:18][CH:19]=[C:20]3[C:29]([CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]4)=[CH:21]3)=[C:16]2[CH:15]=[CH:14][CH:13]=1.[C:30]1([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:37]1([N:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:12]2[C:17]3=[CH:18][CH:19]=[C:20]4[C:29]([CH:28]=[C:27]5[C:22]([CH:23]=[CH:24][CH:25]=[CH:26]5)=[CH:21]4)=[C:16]3[CH:15]=[CH:14][CH:13]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Brc1cccc2c1ccc1cc3ccccc3cc12
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(Cl)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(N(c2ccccc2)c2cccc3c2ccc2cc4ccccc4cc23)cc1
Temperature: 60 °C

Procedure:
190 μl (1 mmol) of chlorodi-tert-butylphosphine and then 112 mg (0.5 mmol) of palladium(II) acetate are added to a suspension of 15.4 g (50 mmol) of 4-bromobenz[a]anthracene, 10.2 g (60 mmol) of diphenylamine and 7.7 g (80 mmol) of sodium tert-butoxide in 500 ml of toluene, and the mixture is subsequently heated under reflux for 5 h. After the mixture has been cooled to 60° C., 500 ml of water are added, the organic phase is separated off, filtered through silica gel, evaporated virtually to dryness at 80° C. in vacuo, and 300 ml of ethanol are then added. After cooling, the solid is filtered off with suction. Recrystallisation five times from dioxane (about 8 ml/g); sublimation (p=5×10−5 mbar, T=280° C.). Yield: 12.7 g (32 mmol), 64.1%, purity 99.9% (HPLC), Tg=74.7° C.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:20]1([CH2:26][CH2:27]Cl)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][CH2:27][O:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][C:8](=[O:18])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCN1CCCCC1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Agent: Cl
Product: O=c1oc2ccccc2c(OCCN2CCCCC2)c1-c1ccccc1
Yield: 73 %

Procedure:
10 g. (0.042 mol) of 3-phenyl-4-hydroxy-coumarin and 10.1 g. (0.55 mol) of 2-piperidino-1-chlorethane hydrochloride are caused to react in the manner described in Example 1. 10.8 g. of a yellow oil are obtained, which cannot be crystallised. Yield 73% (theoretical yield 14.7 g.).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].CC(C)[O-].[La+3:12].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[CH3:2][C:1]([CH2:4][C:5]([CH3:6])=[O:7])=[O:3].[CH3:2][C:1]([CH2:4][C:5]([CH3:6])=[O:7])=[O:3].[CH3:2][C:1]([CH2:4][C:5]([CH3:6])=[O:7])=[O:3].[La:12]
Reactant: [La+3]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)CC(C)=O
Product: [La]
Reaction time: 8 h

Procedure:
Acetylacetone (3 ml) was added dropwise to a solution of lanthanum isopropoxide (0.80 g) in 4 ml of toluene. A white precipitate began to form partway through the addition. Additional toluene was added (4 ml) and the mixture was stirred overnight. The solvent was removed in vacuo and the residue was extracted with acetone. Filtration gave 0.363 g of acetone insoluble solid. The acetone filtrate was concentrated to a pale yellow oil. The oil was extracted with pentane. The pentane solution was filtered and the pentane was removed in vacuo to give a light yellow solid (0.771 g) which was tested for polymerization activity.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7]([N:12]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[CH3:18])=[C:6]([F:19])[C:5]=1[F:20].[OH-].[Na+]>C1COCC1>[CH3:18][C:13]1[N:12]([C:7]2[C:8]([F:11])=[C:9]([F:10])[C:4]([C:3]([OH:21])=[O:2])=[C:5]([F:20])[C:6]=2[F:19])[C:16]([CH3:17])=[CH:15][CH:14]=1
Reactant: COC(=O)c1c(F)c(F)c(-n2c(C)ccc2C)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: 90 °C
Yield: 75.2 %

Procedure:
To the solution of 4-(2,5-dimethyl-pyrrol-1-yl)-2,3,5,6-tetrafluoro-benzoic acid methyl ester (0.6 g, 1.99 mmol) in THF (20 mL) was added an aq. solution of 5 N NaOH (5 mL). The reaction mixture was stirred under refluxed at 90° C. for 3 hours. TLC shows completion of the reaction. The reaction mixture was concentrated and the resulting residue was cooled, acidified with aq, solution of 2 N HCl, extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulphate then concentrated. The resulting residue was purified by washing with hot hexane to get the title compound (0.43 g, 75%). LCMS− m/z 288, 91%
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][N:14]=1)=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][N:14]=2)=[O:12])=[O:29])[N:27]=1
Reactant: O=C(NC[C@H]1NC[C@@H]2CCC[C@@H]21)c1nsc2ccccc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2nsc3ccccc23)c1

Procedure:
prepared by reaction of benzo[d]isothiazole-3-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:27][OH:28])=[N:11][CH:12]=[C:13]([C:25]=1[OH:26])[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:10]([CH:27]=[O:28])=[N:11][CH:12]=[C:13]([C:25]=1[OH:26])[C:14]([NH:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)c1cnc(CO)c(OCc2ccccc2)c1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
After manganese dioxide (49 g) was added to a suspension of the compound 10 (9.8 g, 25.6 mmol) in chloroform (490 ml), the mixture was stirred at room temperature for 1 hour. After the reaction solution was stirred at 60° C. for 20 minutes, Celite filtration was performed, and this was washed with chloroform heated at 50° C. The filtrate was distilled off under reduced pressure to obtain 5-benzyloxy-N-(4-fluoro-benzyl)-6-formyl-4-hydroxy-nicotinic acid amide 12 (8.2 g, 84%) as a pale yellow crystal.