Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([O:9][C:10](=[O:27])[CH2:11][N:12]([C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)([CH3:8])([CH3:7])[CH3:6].C([O-])(=O)C([O-])=O.C([O-])(=O)C.[Na+].[CH2:39]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH2:55][CH2:56][CH2:57][CH2:58][C:59](=O)[C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH2:51][CH2:50]1)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(O)C.C(O)(=O)C>[C:5]([O:9][C:10](=[O:27])[CH2:11][N:12]([C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C@@H:59]([C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH2:58][CH2:57][CH2:56][CH2:55][CH:52]1[CH2:53][CH2:54][N:49]([C:47]([O:46][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:48])[CH2:50][CH2:51]1)[CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)([CH3:6])([CH3:8])[CH3:7]
Reactant: C[C@H](N)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Reactant: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: O=C([O-])C(=O)[O-]
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Reaction time: 8 h
Yield: 8.2 %

Procedure:
A solution of 0.6 g of sodium cyanoborohydride in 50 ml of ethanol is added dropwise to a stirred mixture of 2 g of N-(L-alanyl)-N-(2-indanyl)glycine tert-butyl ester.oxalate, 0.78 g of sodium acetate, 0.58 g of acetic acid, 10 g of molecular sieves 3 A, 3.6 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate and 50 ml of ethanol at room temperature over a period of 3 hours. The reaction solution is allowed to stand overnight and filtered, and the filtrate is concentrated under reduced pressure. The residue is diluted with 50 ml of water and extracted with 200 ml of ethyl acetate. The extract is dried and concentrated under reduced pressure. The resulting oily material is separated and purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to 2:3), whereby the first fraction yields 0.35 g of N-[N-[(R)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[CH:4][C:5]([F:30])=[C:6]([S:8]([N:11]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[F:38][C:39]1[CH:46]=[C:45]([OH:47])[CH:44]=[CH:43][C:40]=1[C:41]#[N:42].O>CS(C)=O.[Cl-].[Na+].O>[Br:1][C:2]1[C:3]([O:47][C:45]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[C:39]([F:38])[CH:46]=2)=[CH:4][C:5]([F:30])=[C:6]([S:8]([N:11]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: N#Cc1ccc(O)cc1F
Reactant: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2cc(Br)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2cc(Br)c(Oc3ccc(C#N)c(F)c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13 %

Procedure:
To a solution of 5-bromo-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Preparation 12, 425 mg, 0.90 mmol) in DMSO (5 mL) was added K2CO3 (372 g, 2.70 mmol) followed by 2-fluoro-4-hydroxybenzonitrile (123 g, 0.90 mmol). The reaction mixture was left to stir at room temperature for 18 hours. To the reaction mixture was added water (20 mL) and saturated brine (20 mL) and the product was extracted with EtOAc (50 mL). The organic layer was retained and washed with saturated brine (3×40 mL), dried over MgSO4, and the solvent removed under vacuum. The residue was purified using silica gel column chromatography eluting with 15% EtOAc in heptanes followed by trituration with heptane to afford the title compound as a colourless solid (74 mg, 28%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[F:12][C:13]1[CH:14]=[C:15]([OH:23])[CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20]>>[F:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[O:23][C:15]1[CH:16]=[CH:17][C:18]([C:19]([F:20])([F:21])[F:22])=[C:13]([F:12])[CH:14]=1)[CH:5]=[O:6]
Reactant: Oc1ccc(C(F)(F)F)c(F)c1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: O=Cc1cc(F)c(Oc2ccc(C(F)(F)F)c(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-fluoro-4-(trifluoromethyl)phenol.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[OH-].[Na+]>[Pd].O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(O)c1cncc(Br)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cncc(-c2ccc(F)cc2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1.38 kg of 5-bromonicotinic acid, 1.10 kg of 4-fluorobenzeneboronic acid and 0.40 kg of Pd/activated carbon (5%) are introduced into 8.5 liters of water. The black suspension is rendered alkaline using 1.39 kg of 32% sodium hydroxide solution and warmed to 100° C. After 4 hours, the mixture is subjected to conventional work-up, giving 5-(4-fluorophenyl)nicotinic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27]1>CN(C=O)C>[CH2:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:27][CH2:28]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1n[nH]c2ccccc12
Temperature: 60 °C
Yield: 85.1 %

Procedure:
A stirred solution of 1-H-indazole-3-carboxylic acid (8.11 g, 50.0 mmol) in dry DMF (140 ml) under argon atmosphere was added CDI (8.92 g, 55 mmol) and heated at 60° C. for 2 h. The mixture was cooled to room temperature, dropwise added 4-amino-1-benzylpiperidine (9.51 g, 50.0 mmol) previously dissolved in DMF (20 ml). The mixture was heated at 60° C. for 2 h, cooled to room temperature and the solvent evaporated in vacuo. The residue was added CH2Cl2 (250 ml) and the organic layer washed with H2O (100 ml), 1 N aqueous NaOH (100 ml), H2O (100 ml) and brine (100 ml). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue was recrystalilized from EtOH to leave the expected product as a white solid (14.23 g, 85.1%).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H](N)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@H](C(=O)N(C)C)C2CCCCC2)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.54 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 256-2 (5.50 mmol, crude form) as starting materials, respectively 0.97 g (Isomer A, colorless powder) and 1.44 g (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:11])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Li+]>O1CCCC1.O>[CH3:11][C:5]1([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(C)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCOCC1
Temperature: 50 °C
Yield: 90.5 %

Procedure:
A solution of 4-methyl-tetrahydro-pyran-4-carboxylic acid methyl ester (3.64 g, 23 mmol) in tetrahydrofuran (136 ml) was treated with a solution of lithium hydroxide (4.83 g, 115 mmol) in deionized water (27 ml). The reaction mixture was heated to 50° C. for overnight and then partitioned between EtOAc/water. The aqueous phase was collected and then partitioned between EtOAc/ice cold 1N HCl. The organic layers were dried over MgSO4, filtered, and concentrated providing 3 grams (90%) of 4-methyl-tetrahydro-pyran-4-carboxylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:22])C(=O)C1.CCOC(C)=O.O>C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[Br:22][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccc(CC(=O)O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(Br)C(=O)O)cc1
Temperature: 70 °C
Yield: 99.3 %

Procedure:
To a stirring solution of (4-tert-butyl-phenyl)-acetic acid (1.5 g, 7.8 mmol) in benzene (30 mL) at room temperature was added NBS (1.39 g, 7.8 mmol) and AIBN (15 mg, 0.08 mmol). The mixture was heated at 70° C. for 16 hrs, added EtOAc and water. The organic layer was collected and dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude bromo-(4-tert-butyl-phenyl)-acetic acid as a light yellow solid (2.1 g, 99%): 1H NMR (300 MHz, DMSO-d6): 7.46 (m, 4H), 5.74 (s, 1H), 1.29 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[N:23]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.Cl.O1CCOCC1>>[Cl:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)[N:23]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cccc(CNc2cccc(-c3cc(NC4CCNCC4)ncc3Cl)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 141.1 %

Procedure:
A mixture of tert-butyl 4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)piperidine-1-carboxylate (220 mg, 0.430 mmol), HCl 4M in Dioxane (7 mL, 28.0 mmol) was stirred at ambient temperature for 1 hr. The solvent was evaporated under reduced pressure to yield a solid which was further dried under high vacuum to yield 250 mg of the title compound as a HCl salt. A portion of the title compound was purified by prep LC, and then lyapholized to yield 19.0 mg of the title compound as a TFA salt. LCMS (m/z): 412.2 (MH+), retention time=0.60 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.). 6 ppm 1.66-1.83 (m, 2H) 2.25 (dd, J=14.21, 3.08 Hz, 2H) 3.08-3.21 (m, 2H) 3.36-3.51 (m, 2H) 3.96-4.12 (m, 1H) 4.65 (s, 2H) 6.74 (s, 1H) 6.91 (s, 1H) 6.94 (s, 1H) 6.98-7.06 (m, 1H) 7.12 (d, J=9.96 Hz, 1H) 7.19 (d, J=7.62 Hz, 1H) 7.31-7.43 (m, 1H) 7.77-7.85 (m, 1H) 8.09 (s, 1H)
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13]([O-:17])(=[O:16])(=[O:15])=[O:14].CS[C:20]1[S:24][CH:23]=[CH:22][S+:21]=1>>[Cl:13]([O-:17])(=[O:16])(=[O:15])=[O:14].[S:21]1[CH:22]=[CH:23][S:24][C:20]1=[N+:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CSc1scc[s+]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: c1ccc(N2CC[N+](=c3sccs3)CC2)cc1
Yield: 74 %

Procedure:
2.0 g of N-phenylpiperazine and 2.5 g of 2-methylthio-1,3-dithiolium perchlorate were treated in the same manner as in Example 26, and the product was recrystallized from acetone-ethyl ether, whereby 2.7 g (yield: 74.3%) of 1-(1,3-dithiol-2-ylidene)-4-phenylpiperazinium perchlorate (Compound No. 32) was obtained as crystals having a melting point of from 197° to 199° C.
Reaction SMILES: [Na].[CH2:2]([N:4]([CH2:26][CH2:27][CH2:28][CH3:29])[C:5]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[N:12]([C:17]3[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=3[Cl:25])[N:13]=[C:14]([S:15][CH3:16])[C:6]=12)[CH3:3].[CH3:30][OH:31]>>[CH2:2]([N:4]([CH2:26][CH2:27][CH2:28][CH3:29])[C:5]1[N:10]=[C:9]([O:31][CH3:30])[N:8]=[C:7]2[N:12]([C:17]3[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=3[Cl:25])[N:13]=[C:14]([S:15][CH3:16])[C:6]=12)[CH3:3]
Reactant: CCCCN(CC)c1nc(Cl)nc2c1c(SC)nn2-c1c(Cl)cc(Cl)cc1Cl
Reactant: CO
Agent: [Na]
Product: CCCCN(CC)c1nc(OC)nc2c1c(SC)nn2-c1c(Cl)cc(Cl)cc1Cl

Procedure:
To 1 ml of methanol was added sodium (25 mg) and the mixture was stirred until all the sodium was dissolved completely. The resulting solution was treated with ethyl-butyl-[6-chloro-3-methylsulfanyl-1-(2,4,6trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-yl]amine (100 mg, 0.21 mmol) and heated at reflux for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give an oil residue. The oil residue was purified by silica gel column chromatography to give 73 mg of the title compound as a colorless oil. 1H NMR (CDCl3):0.96(t,3H), 1.35(t,3H), 1.42(m,2H), 1.71(m,2H), 2.63(s,3H), 3.74(dd,2H), 3.86(q,2H), 3.91(s,3H), 7.46(s,2H)ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:13]([N:17]1[C:25]2[N:24]=[C:23]([Cl:26])[NH:22][C:21]=2[C:20](=[O:27])[N:19]([CH2:28][CH2:29][CH2:30]/[C:31](=[N:34]/[H])/[NH:32]O)[C:18]1=[O:36])[CH2:14][CH2:15][CH3:16]>CS(C)=O>[CH2:13]([N:17]1[C:25]2[N:24]=[C:23]([Cl:26])[NH:22][C:21]=2[C:20](=[O:27])[N:19]([CH2:28][CH2:29][CH2:30][C:31]2[N:32]=[C:10]([CH2:9][C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=3)[O:12][N:34]=2)[C:18]1=[O:36])[CH2:14][CH2:15][CH3:16]
Reactant: [H]/N=C(/CCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCc2noc(Cc3ccc(O)c(Cl)c3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 120 °C
Yield: 18.7 %

Procedure:
A solution of 3-chloro-4-hydroxyphenylacetic acid (24 mg, 0.13 mmol) in DMSO (1 ml) was treated with CDl (21 mg, 0.13 mmol) and left to react for 30 min. (1Z)-4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide (50 mg, 0.15 mmol) was added and the mixture heated in the microwave at 120° C. for 15 min. The solution was directly purified by MDAP to obtain the title compound as a white solid (12 mg, 17%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C@@H:13](O)[CH2:12][N:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].CCN(S(F)(F)[F:29])CC>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C@H:13]([F:29])[CH2:12][N:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1c1cc(F)cc(C#N)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1c1cc(F)cc(C#N)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,4R)-tert-butyl 2-(3-cyano-5-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (I-13A) (0.7 g, 2.3 mmol) in DCM (4 mL) in a plastic bottle at −78° C. was added DAST (0.6 mL, 4.6 mmol). The reaction was stirred at −78° C. for 2 hours and then loaded directly onto silica gel and purified by column chromatography with EtOAc/hexanes gradient as eluant to yield (2R,4S)-tert-butyl 2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidine-1-carboxylate (I-14). 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1 H), 7.30-7.16 (m, 2 H), 5.25 (d, J=52.0 Hz, 1 H), 5.06-4.86 (m, 1 H), 4.20-3.98 (m, 1 H), 3.72 (dd, J=11.6, 38.8 Hz, 1 H), 2.80-2.66 (m, 1 H), 2.06-1.78 (m, 1 H), 1.45 (bs, 3 H), 1.19 (bs, 6 H). MS m/z 331.1 (M+23)+.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Br:8][C:9]1[C:13]([Br:14])=[CH:12][S:11][CH:10]=1.ICCC>C1COCC1.CCCCCC>[Br:8][C:9]1[C:13]([Br:14])=[CH:12][S:11][C:10]=1[CH2:7][CH2:5][CH3:6]
Reactant: CC(C)NC(C)C
Reactant: Brc1cscc1Br
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCCI
Product: CCCc1scc(Br)c1Br
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of diisopropylamine (2.7 mL, 19.4 mmol) in 50 mL of THF cooled to -78° C. was added 7.8 mL (2.5M in hexane, 19.4 mmol) of nbutyllithium, and the reaction was stirred for 0.5 hours. To the first solution was added 4.7 g (19.4 mmol) of 3,4-dibromothiophene (Aldrich), then the reaction mixture was stirred for 1 hour at -78° C. Iodopropane (2.8 mL, 29.1 mmol) was then added, the reaction stirred for 10 min at -78° C., then removed for the cooling bath and stirred for 2 hours at room temperature. The reaction was quenched with aqueous satd. NH4Cl, extracted with ether, washed with H2O and brine, and concentrated to give 5.27 g of crude 3,4-dibromo-2-propylthiophene. This compound (5.25 g, 18.5 mmol) was dissolved in 80 mL of ether and cooled to -78° C. n-Butyllithium (7.4 mL, 18.5 mmol) was added dropwise via syringe, and the resulting mixture was stirred at -78° C. for 20 min. DMF was added (1.86 mL, 24.03 mmol), and the reaction was stirred at -78° C. for 1 hour, then poured into water and extracted with ether. The extract was washed with water, dried over MgSO4, and concentrated in vacuo. Silica gel column chromatography afforded 0.63 g of the title compound. NMR (CDCl3) δ:10.07 (s, 1H), 7.09 (s, 1H), 3.20 (t, J=7 Hz, 2H), 1.74 (m, 2H), 1.02 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH3:10])=[O:8])=[CH:5][C:4]=1[CH3:24])#[N:2].[BH4-].[Na+].N>CO.O.O.O.O.O.O.[Co+2]>[NH2:2][CH2:1][C:3]1[CH:23]=[CH:22][C:6]([C:7]([N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH3:10])=[O:8])=[CH:5][C:4]=1[CH3:24]
Reactant: Cc1cc(C(=O)N(C)c2ccccc2-c2ccco2)ccc1C#N
Agent: [Co+2]
Agent: N
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)N(C)c2ccccc2-c2ccco2)ccc1CN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-cyano-N-(2-furan-2-ylphenyl)-3,N-dimethylbenzamide from Example 21C (198 mg, 0.626 mmol) in methanol (10 ml) was added cobalt (II) hexahydrate (300 mg, 1.25 mmol). The mixture was cooled in an ice/water bath and sodium borohydride (237 mg, 6.26 mmol) was added portionwise. The mixture was allowed to warm to room temperature and stirred for 2 h. Ammonia solution (4.0 ml) was added and the mixture stirred for 30 min, filtered through Celite® and evaporated in vacuo. The residue was taken up in chloroform and brine, filtered through Celite®, separated and the organic layer was dried and evaporated in vacuo to give a white solid; yield 200 mg, 100%.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:29])[CH:27]=[CH2:28]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:26](=[O:29])[CH:27]=[CH2:28])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CC(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Acryloyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol- 2-yl)-3-methyl-6-acryloyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: C=O.[C:3](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:17]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH:18]1[CH2:26][NH:27][C:28]([C:30]1[C:31]([NH:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([Cl:52])[CH:45]=2)=[N:32][C:33]([N:36]2[CH2:41][CH:40]3[CH:38]([CH2:39]3)[CH2:37]2)=[N:34][CH:35]=1)=[O:29]>C1COCC1>[CH:38]12[CH2:39][CH:40]1[CH2:41][N:36]([C:33]1[N:32]=[C:31]([NH:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([Cl:52])[CH:45]=3)[C:30]([C:28]([NH:27][CH2:26][CH:18]3[CH2:19][C:20]4([CH2:21][CH2:22][N:23]([CH3:3])[CH2:24][CH2:25]4)[CH2:17]3)=[O:29])=[CH:35][N:34]=1)[CH2:37]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCC2CC3(CCNCC3)C2)cc1Cl
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCC2CC3(CCN(C)CC3)C2)cc1Cl
Reaction time: 1 h
Yield: 21 %

Procedure:
In THF (20 mL) was dissolved the above N-(7-azaspiro[3.5]nonan-2-ylmethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-formamide. Formalin (1 mL) was added. The reaction was conducted at ambient temperature for 1 h, sodium triacetoxyborohydride (134 mg, 0.63 mmol) was added and the reaction was continued for 4 h. The reaction was quenched with water. The reaction mixture was filtrated. The organic phase was dried and concentrated. The obtained solid was purified by silica gel column chromatography (DCM/methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-((7-methyl-7-azaspiro[3.5]nonan-2-yl)methyl) pyrimidine-5-formamide (39 mg, 21% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][S:43](CN1C=CC(N)=N1)(=[O:45])=[O:44]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][S:43]([CH3:42])(=[O:45])=[O:44])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: CS(=O)(=O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (166 μL, 0.33 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (46 μL, 0.39 mmol) was added to the solution at 0° C. After 1 h, 1-methanesulfonylmethyl-1H-pyrazol-3-ylamine (0.30 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-methanesulfonylmethyl-1H-pyrazol-3-yl)-propionamide (133 mg, 90%) as a white solid: ESI-LRMS m/e calcd for C20H26ClN3O5S2 [M+] 487.1, found 488.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.22 (m, 2H, CH2), 1.43-1.94 (m, 8H, 4×CH2), 2.09-2.29 (m, 1H, CH), 2.86 (s, 3H, SO2CH3), 3.27 (s, 3H, SO2CH3), 3.58 (t, J=7.5 Hz, 1H, CH), 5.25 (s, 2H, NCH2), 6.87 (d, J=2.5 Hz, 1H, Ar), 7.48 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.54 (d, J=2.5 Hz, 1H, Ar), 7.61 (d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.1 Hz, 1H, Ar), 8.10 (brs, 1H, NH).