Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].Cl>C(Cl)Cl>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 83 %

Procedure:
To a suspension of glycine ethyl ester hydrochloride (9.45 g) in methylene chloride (100 ml) were added triethylamine (18.9 ml) and 2-nitrobenzenesulfonyl chloride (10.0 g) in succession under cooling with ice and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added 1N hydrochloric acid under cooling with ice, followed by extraction with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate, then saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the precipitated crystals were washed with a mixed solvent of n-hexane and diethyl ether, collected by filtration and air-dried to obtain the title compound (10.8 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[S:10][C:9](=[NH:11])[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:7]=1.[CH2:19]1[CH:26]2[C:22]3([C:28](O)=[O:29])[CH2:23][CH:24]([CH2:27][CH:20]1[CH2:21]3)[CH2:25]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[S:10][C:9](=[N:11][C:28]([C:22]23[CH2:23][CH:24]4[CH2:27][CH:20]([CH2:19][CH:26]2[CH2:25]4)[CH2:21]3)=[O:29])[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:7]=1
Reactant: COCCn1cc(Cc2cccc(F)c2)sc1=N
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCn1cc(Cc2cccc(F)c2)sc1=NC(=O)C12CC3CC(CC1C3)C2

Procedure:
A mixture of the product of Example 45A (342 mg, 1.29 mmol), hexahydro-2,5-methano-pentalene-3a-carboxylic acid (256 mg, 1.54 mmol), HATU (737 mg, 1.24 mmol) and triethylamine (1.08 mL, 7.74 mmol) in 20 mL of DMF was processed according to the method of Example 43B to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ 1.50-1.61 (m, 4 H), 1.65-1.76 (m, 4 H), 2.03-2.11 (m, 2 H), 2.21-2.26 (m, 2 H), 2.48-2.55 (m, 1 H), 3.25 (s, 3 H), 3.68 (t, J=5.4 Hz, 2 H), 3.99 (s, 2 H), 4.25 (t, J=5.4 Hz, 2 H), 7.03-7.13 (m, 3 H), 7.26 (s, 1 H), 7.33-7.41 (m, 1 H); MS (DCI/NH3) m/z 415 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:4].[N-:19]=[N+:20]=[N-:21].[Na+].[CH:23](OCC)(OCC)OCC>CC(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([N:11]2[CH:23]=[N:21][N:20]=[N:19]2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2cnnn2)c1
Yield: 91.9 %

Procedure:
To a solution of 5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (10 g, 41.5 mmol) and NaN3 (4.99 g, 76.76 mmol) in AcOH (80 mL) was added HC(OEt)3 (29.5 g, 199.2 mmol) at room temperature, then heated to reflux for 4 h. The solvent was removed in vacuo and the residue was purified by silica-gel chromatography to give 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid methyl ester as light yellow solid (11.22 g, 92%). MS (M+H)=295.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=1)(C(OCC=C)=O)[C:18]([O:20]CC=C)=[O:19])#[N:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:18]([CH:17]([CH2:16][CH2:15][CH2:14][CH2:13][C:11]#[N:12])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=1)([OH:20])=[O:19]
Reactant: C=CCOC(=O)C(CCCCC#N)(CCc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCC(CCCCC#N)C(=O)O)cc1
Temperature: 10 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
A solution of 7.45 ml (53.42 mmol) of triethylamine and 1.53 ml (40.47 mmol) of formic acid in 67 ml of dioxane is added to a solution of 6.92 g (16.19 mmol) of diallyl 2-(4-cyanobutyl)-2-[2-(4-methoxycarbonylphenyl)ethyl]malonate from Example 91A, 594 mg (2.26 mmol) of triphenylphosphine and 145 mg (0.64 mmol) of palladium acetate in 67 ml of dioxane at room temperature. The reaction mixture is then stirred at 10° C. for 12 hours. After conversion is complete, the reaction solution is cooled and the solvent is removed in vacuo. The residue is taken-up in ethyl acetate and water and acidified with 1 N hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted three times with ethyl acetate, and the organic phases are then combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the organic phase is concentrated in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1→1:3, with 1% formic acid). 2.1 g (43% yield, 100% purity) of a colorless solid are obtained.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[CH3:7][S:8]([C:10](SC)=[CH:11][N+:12]([O-:14])=[O:13])=O>CO>[CH3:7][S:8][C:10]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:11][N+:12]([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: NCC(F)(F)F
Solvent: CO
Product: CSC(=C[N+](=O)[O-])NCC(F)(F)F

Procedure:
A solution of 2,2,2-trifluoroethylamine (4.0 g) in methanol (45 ml) was added dropwise to a suspension of 1-methylsulphinyl-1-methylthio-2-nitroethylene (3.6 g) in methanol (150 ml) at 20° for 24 hours. Evaporation of the reaction mixture and recrystallisation from ether gave the title compound as a pale orange crystalline solid m.p. 101°-102°.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:35])[CH2:7][CH2:8][NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:34])/[CH:19]=[CH:20]/[CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:13]1)=[O:11])C.O1CCCC1.C(O)C>O>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][CH:21](/[CH:20]=[CH:19]/[C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:35])=[O:5])=[O:11])[CH2:13]2)=[O:34])[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)CCNC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)NCCC(=O)O)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A solution of LiOH (0.18 g) in water (10 ml) was added to a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-β-alanine ethyl ester (1.74 g) in the mixture of tetrahydrofuran (10 ml) and ethanol (10 ml) at 0° C. The reaction mixture was stirred for overnight at room temperature, and the solvent was evaporated in vacuo. The residue was resolved in ethyl acetate-water, and acidified with 10% aqueous KHSO4. The whole was washed with water, brine, dried over MgSO4, and evaporated in vacuo to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-β-alanine as a colorless oil (1.64 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-])=O.NC1C=CC=CC=1>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1Oc1cc(F)cc(F)c1
Solvent: Nc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc(N)ccc1Oc1cc(F)cc(F)c1
Yield: 100.9 %

Procedure:
Using the method of Example 17.3, ethyl 5-nitro-2-(3,5-difluorophenoxy)benzoate (0.76 g) in ethanol (7 mL) and TBF (3 mL) was converted to the corresponding aniline derivative which was obtained as an oil (0.696 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)#[N:7]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CCOC(=O)c1ccc(CCNC)cc1
Product: CCOC(=O)c1ccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1

Procedure:
Reaction of 1f with 2c produced 3r. MS found M+H=467. The oxalate salt of 3r was recrystallized from ethyl acetate; mp 111-112° C.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:25]1(=[O:30])[CH2:29][CH2:28][CH:27]=[CH:26]1.CN(C1CCCCC1)C1CCCCC1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([C:27]3[CH2:28][CH2:29][C:25](=[O:30])[CH:26]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: O=C1C=CCC1
Reactant: Brc1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: O=C1C=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A solution of N-(4-(3-bromopyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (600 mg, 1.506 mmol), 2-cyclopenten-1-one (0.609 mL, 7.53 mmol), n-methyldicyclohexylamine (0.959 mL, 4.52 mmol) and bis(tri-tert-butylphosphine)palladium (0) (77 mg, 0.151 mmol) in Dioxane (4 mL) was capped, degassed and backfilled with argon. The reaction was heated to 90° C. After 6 h, the reaction was heated to 110° C. After 36 h, the reaction was cooled to 23° C., diluted with EtOAc (150 mL) and washed with water (100 mL) and brine (100 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 0.5-3% methanol/dichloromethane), affording the product as a yellow solid. MS (ESI, pos. ion) m/z: 400.1 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:8]=1[O:9]/[C:10](=[CH:14]\[C:15]([OH:17])=O)/[C:11]([OH:13])=[O:12].[CH2:24](O)[CH3:25]>>[Br:6][C:7]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]2[C:8]=1[O:9][C:10]([C:11]([O:13][CH2:24][CH3:25])=[O:12])=[CH:14][C:15]2=[O:17]
Reactant: COc1ccc(O/C(=C\C(=O)O)C(=O)O)c(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(=O)c2cc(OC)cc(Br)c2o1
Yield: 50 %

Procedure:
Sulfuric acid (50 ml) was added to (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioic acid (24.3 g, 86.6 mmol; as prepared in Reference Example 2b above). After heating the mixture with a heat gun for 5-10 min a clear deep brown solution was obtained. This solution was slowly added to refluxing absolute ethanol (250 ml). After the addition the reaction was refluxed for 30 min then allowed to cool. Crystals started to form after 20 min and the reaction was put in the refrigerator overnight. The solid was filtered, washed with cold ethanol/water 9:1 and dried to give ethyl 8-bromo-6-methoxy-4-oxo-4H-chromene-2-carboxylate as an off-white solid (12.3 g, 50% yield, mp 159-161° C.).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][CH2:28][NH2:29].[F:30][C:31]1[CH:49]=[CH:48][C:34]([CH2:35][N:36]([CH3:47])[C:37]([C:39]2[CH2:40]N(C)[C:42](=[O:45])[C:43]=2[OH:44])=[O:38])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:49]=[CH:48][C:34]([CH2:35][N:36]([CH3:47])[C:37]([C:39]2[CH2:40][N:29]([CH2:28][CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[C:42](=[O:45])[C:43]=2[OH:44])=[O:38])=[CH:33][CH:32]=1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Reactant: NCCc1cccs1
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2cccs2)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-thiophen-2-yl-ethylamine as described in the preparation of Compound 1. HRMS (M−H) calcd for C19H18FN2O3S: 373.1022. found: 373.1029. 1H NMR (500 MHz, CDCl3) δ: 2.95 (s, 3), 3.14 (t, 2, J=7), 3.76 (t, 2, J=7), 3.97 (s, 2), 4.57 (s, 2), 6.81–7.21 (overlapping m, 7). 13C NMR (125 MHz, CDCl3) δ: 28.76, 34.49, 44.93, 49.46, 51.47, 109.48, 115.65, 115.82, 124.20, 125.59, 127.15, 129.28, 129.34, 132.12, 132.14, 140.34, 152.72, 161.37, 163.33, 164.94, 166.11.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:33][C@H:34]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:46][CH:45]=1)[CH2:35][C@:36]([CH2:41][OH:42])([CH3:40])[C:37]([OH:39])=[O:38]>CCN(C(C)C)C(C)C.CN(C=O)C>[C:47]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:46]=[CH:45][C:44]([CH2:43][C@@H:34]([NH:33][C:6]([C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[O:8])[CH2:35][C@:36]([CH2:41][OH:42])([CH3:40])[C:37]([OH:39])=[O:38])=[CH:49][CH:48]=1
Reactant: O=C(O)c1c[nH]nn1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)O
Reaction time: 0.25 h
Yield: 30.7 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (130 mg, 1.2 mmol, 1.2 eq.) and HATU (400 mg, 1.1 mmol, 1.1 eq.) were dissolved in DIPEA (167 μL) and the resulting mixture was stirred for 5 minutes at room temperature in DMF (0.2 mL). DIPEA (3 eq.) and (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (300 mg, 957 μmol, 1.0 eq.) dissolved in DMF (0.2 mL) was added, and the resulting mixture was stirred for 15 minutes. The reaction was quenched with AcOH and the product was purified by preparative HPLC then lyophilized to yield the title compound (120 mg, 95% purity). MS m/z [M+H]+ calc'd for C22H24N4O4, 409.18. found 409.4.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]2=[CH:8][N:9]=1)(=O)[CH3:2].[BH3-]C#[N:22].[Na+]>CO>[NH2:22][CH:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]2=[CH:8][N:9]=1)[CH3:2]
Reactant: CC(=O)c1cc2ccn(C(=O)OC(C)(C)C)c2cn1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cc2ccn(C(=O)OC(C)(C)C)c2cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.3 %

Procedure:
A sealed-cap vial was charged with tert-butyl 5-acetyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (225 mg, 0.86 mmol), NH4OAc ammonium acetate (666 mg, 8.6 mmol), NaBH3CN (71 mg, 1.1 mmol) and MeOH (7 mL). The reaction was stirred at RT for 24 h, after which additional NH4OAc (333 mg, 4.3 mmol) and NaBH3CN (27 mg, 0.43 mmol) were added. The reaction mixture was stirred for another 24 h then concentrated in vacuo. The residue was partitioned between 2N NaOH and EtOAc. The aqueous layer was thrice extracted with EtOAc. The organic extracts were combined and dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with a mixture of EtOAc containing 1% TEA and MeOH to afford 95 mg (42%) of tert-butyl 5-(1-aminoethyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate: MS (ESI) m/z: 262.2 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]([CH3:27])[CH3:26]>C(#N)C>[CH2:24]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[C:8]=2[OH:17])[CH2:3][CH2:2]1)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)CBr
Reactant: Oc1c(C2CCNCC2)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CN1CCC(c2cccc(C(F)(F)F)c2O)CC1

Procedure:
Preparation according to Example 1: 2-piperidin-4-yl-6-(trifluoromethyl)phenol (0.01 g, 0.04 mmol), acetonitrile (2 ml), potassium carbonate (0.01 g) and isobutyl bromide (0.01 ml). MS m/z (relative intensity, 70 eV) 301 (M+, 4), 259 (13), 258 (bp), 238 (9), 194 (11).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]=O)[CH2:3][CH2:2]1.ClCCl.[CH2:10]([O:12][C:13]([C@H:15]1[C@@H:20]([NH2:21])[C@H:19]2[CH2:22][C@@H:16]1[CH2:17][CH2:18]2)=[O:14])[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[CH2:10]([O:12][C:13]([C@H:15]1[C@@H:20]([NH:21][CH2:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[C@H:19]2[CH2:22][C@@H:16]1[CH2:17][CH2:18]2)=[O:14])[CH3:11]
Reactant: O=CCC1CC1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC1CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84.9 %

Procedure:
A 1.4 M solution of cyclopropylacetaldehyde in dichloromethane (prepared as described in Example 23a, 3.4 mL, 4.76 mmol) was added to a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 580 mg, 3.17 mmol) in anhydrous methanol (15 mL) at 25° C. under a nitrogen atmosphere. After stirring for 20 min, glacial acetic acid (0.6 mL) was added. The solution was cooled to 0° C., sodium triacetoxyborohydride (1.7 g, 7.93 mmol) was added, and the resulting mixture was stirred at 25° C. for 20 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (25 mL) and was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with saturated aqueous brine solution, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, (1S,2R,3S,4R)-3-(2-cyclopropyl-ethylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (676.4 mg, 2.69 mmol, 84.9%), as a yellow oil. LC-MS (ESI) calcd for C15H25NO2 251.19, found 252.0 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl.[N:17]([O-])=O.[Na+].[C:21](#[N:25])[CH2:22][C:23]#[N:24].C([O-])(=O)C.[Na+]>>[CH3:15][C@H:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][N:17]=[C:22]([C:21]#[N:25])[C:23]#[N:24])=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=N[O-]
Reactant: N#CCC#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: C[C@@H]1CC(=O)NN=C1c1ccc(NN=C(C#N)C#N)cc1
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
To a solution of (−)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone (20 g) and dilute hydrochloric acid (52 ml of concentrated hydrochloric acid in 789 ml of water), 8 g of dilute sodium nitrite (8 g of sodium nitrite in 52 ml of water) was added and stirred. After 10 minutes, malononitrile solution (6.3 g malononitrile in 52 ml of water) was added. The solution was stirred for 1 hour at room temperature. The pH of the suspension was adjusted to 6.0 with sodium acetate solution. The suspension was filtered, washed with water followed by ethanol and then dried to obtain solid levosimendan (yield—22 g, purity—99.9%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([OH:26])=O)=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][NH2:41].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([NH:41][CH2:40][C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=5)=[O:26])=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[N:3]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(-c5ccc(C(=O)O)nc5)cc4C3)nc(N)n2)CC1
Reactant: NCc1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2cc(N3CCc4ccc(-c5ccc(C(=O)NCc6ccccn6)nc5)cc4C3)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (15 mg, 0.034 mmol) and 2-pyridinemethanamine (7.3 mg, 0.067 mmol, Aldrich, Cat. No. A65204) in N,N-dimethylformamide (1 mL) were added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (21 mg, 0.040 mmol, NovaBiochem, Cat. 01-62-0016) and N,N-diisopropylethylamine (18 μL, 0.10 mmol). The resulting mixture was stirred at r.t. for two hours. Then the reaction solution was diluted in MeOH and purified by RP-HPLC (pH=10 system) to afford the desired compound. LCMS(M+H)+: m/z=536.4.
Reaction SMILES: [CH2:1]([N:6]1[C:10](=[O:11])[CH:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][CH:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[CH2:1]([N:6]1[C:10](=[O:11])[CH:9]([CH:12]([CH3:25])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][CH:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CCOC(=O)CC1SC(c2ccccc2)N(CCC(C)C)C1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C1SC(c2ccccc2)N(CCC(C)C)C1=O
Reaction time: 16 h
Yield: 13.7 %

Procedure:
To a stirred solution of ethyl 2-(3-isopentyl-4-oxo-2-phenylthiazolidin-5-yl)acetate (84 mg, 0.25 mmol) in THF at 0° C. was added LiHMDS (0.28 ml of 1 N, 0.28 mmol) dropwise and the reaction mixture was stirred from 0° C. to RT over 16 hours. The reaction mixture was poured in to 1 N HCl and extracted with EtOAc (4×). The organics were combined, dried (MgSO4) and evaporated to dryness. Purification by preparative TLC (7:1; Hx:EtOAc) gave the desired product as an oil (12 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[NH2:19]>>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[C:3]=1[C:4]([NH:19][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[CH3:12])=[O:6]
Reactant: CC1CCCCC1N
Reactant: Cc1cccc(C)c1C(=O)O
Product: Cc1cccc(C)c1C(=O)NC1CCCCC1C
Yield: 59 %

Procedure:
Prepared in a similar manner to Example 162 using 2,6-dimethylbenzoic acid and 2-methylcyclohexylamine. Yield: 59%. 1H NMR (500 MHz, CDCl3): δ 0.88-0.94 (3H, dd), 1.14-1.89 (9H, m), 2.21-2.22 (6H, d), 3.39-3.45 (1H, m), 7.02-7.03 (2H, d), 7.12-7.15 (1H, t), 8.11-8.13 (1H, d). MS (M+H, 246.2).