Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([N:23]2[CH2:29][CH:28]3[NH:30][CH:25]([CH2:26][CH2:27]3)[CH2:24]2)[C:3]=1[C:31](=[O:33])[CH3:32].[N:34]1[N:35]=[C:36]([C:39](O)=[O:40])[NH:37][CH:38]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:34]1[N:35]=[C:36]([C:39]([N:30]2[CH:28]3[CH2:27][CH2:26][CH:25]2[CH2:24][N:23]([C:4]2[C:3]([C:31](=[O:33])[CH3:32])=[C:2]([NH2:1])[N:7]4[N:8]=[CH:9][C:10]([C:11]5[CH:12]=[N:13][C:14]([C:17]6[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=6)=[CH:15][CH:16]=5)=[C:6]4[N:5]=2)[CH2:29]3)=[O:40])[NH:37][CH:38]=1
Reactant: CC(=O)c1c(N2CC3CCC(C2)N3)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reactant: O=C(O)c1nnc[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1c(N2CC3CCC(C2)N3C(=O)c2nnc[nH]2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(7-amino-5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (11 mg, 0.025 mmol), 4H-1,2,4-triazole-3-carboxylic acid (3.1 mg, 0.027 mmol), EDCI (9.5 mg, 0.05 mmol), HOBt (6.75 mg, 0.05 mmol) and DIEA (26 ul, 0.15 mmol) in DMF (1 ml) was stirred at room temperature overnight. Purification with prep-LC provided 1-(5-(8-(4H-1,2,4-triazole-3-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-amino-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone, LCMS tR=3.31 Min (10 min run, UV 254 nm). Mass calculated for M+H 535.2, observed LC/MS m/z 534.95 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[C:20]([O:24][C:25](=[O:31])[N:26]([CH3:30])[CH2:27][CH:28]=O)([CH3:23])([CH3:22])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:20]([O:24][C:25](=[O:31])[N:26]([CH2:27][CH2:28][N:17]1[CH2:16][CH2:15][N:14]([C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:13][CH:12]=[CH:11][N:10]=2)[CH2:19][CH2:18]1)[CH3:30])([CH3:23])([CH3:22])[CH3:21]
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(CCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (2.5 g, 9.7 mmol, 1 eq.) in 1,2 dichloroethane (20 mL). Add methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (1.77 g, 10.19 mmol, 1.05 eq.). Add sodium triacetoxy-borohydride (3.10 g, 14.6 mmol, 1.5 eq.). Stir at room temperature for 18 hr. Partition the reaction mixture between aqueous saturated NaHCO3 and dichloromethane. Separate the layers. Extract the organic layer with dichloromethane (2×100 mL). Combine the organic layers, dry over anhydrous Na2SO4, filter and concentrate. Purify by normal phase chromatography with 30% EtOAc/hexane—100% EtOAc to afford the title preparation (3.8 g, 97% yield). MS (loop): m/z=416.3 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][NH:19][CH:20]4[CH2:23][O:22][CH2:21]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1.BrC1C=CC2OCCN3C(CN4CCCC4)=C(C(N)=O)N=C3C=2C=1.NC1COC1.[CH3:54][C:55]([OH:59])([C:57]#[CH:58])[CH3:56]>>[OH:59][C:55]([CH3:56])([CH3:54])[C:57]#[C:58][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][NH:19][CH:20]4[CH2:21][O:22][CH2:23]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2n(c1CNC1COC1)CCOc1ccc(Br)cc1-2
Agent: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Agent: NC1COC1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(CNC3COC3)n1CCO2
Yield: 17 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((oxetan-3-ylamino)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carb oxamide (prepared similarly as described in the synthesis of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing pyrrolidine with 3-aminooxetane) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a brown solid (17 mg, 17%).
Reaction SMILES: CC1OC=CC=1.O1C=CC=C1.[Li].[CH3:13][C:14]1[O:15][C:16]([SH:19])=[CH:17][CH:18]=1.Cl[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CCOCC>[CH3:13][C:14]1[O:15][C:16]([S:19][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S)o1
Reactant: COC(=O)CCl
Agent: Cc1ccco1
Agent: [Li]
Solvent: c1ccoc1
Solvent: CCOCC
Product: COC(=O)CSc1ccc(C)o1
Reaction time: 48 h

Procedure:
The necessary starting material was prepared from 2-methylfuran (16.4 g) by an analogous procedure to that described for furan itself in Example 14, except that in this case the intermediate lithium salt of 2-methylfuran-5-thiol was reacted in dry ether at -20° C. with methyl 2-chloroacetate. The reaction mixture was stirred for 2 days and then partitioned between water (800 ml) and ether (3×400 ml). The organic layers were dried (MgSO4) and evaporated. The residual oil was distilled to give methyl 2-(2-methylfur-5-ylthio)acetate (40.1 g) b.p. 94°-96° C./0.5 mm; NMR (90 MHz): 2.30 (s,3H), 3.45 (s,2H), 3.70 (s,3H), 5.95 (m,1H), 6.45 (d,1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)C1C=CC=CC=1>CO.[Rh]>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1CCc1ccc(CO)cc1
Agent: [Rh]
Solvent: CO
Product: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 10.0 g (29.8 mmol) 4-benzyloxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2a) in 150 mL MeOH is added 1.50 g Rh/C. The reaction mixture is stirred under a hydrogen atmosphere of 3000 hPa at RT for 20 h. 300 mL MeOH is added and the mixture is heated to reflux. The catalyst is removed by filtration and the solvent is removed almost completely. After cooling to RT, the precipitate is collected and dried in vacuo at 40° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[C:16]([C:18]1[CH:19]=[C:20]([NH:25]N)[CH:21]=[CH:22][C:23]=1[F:24])#[N:17]>>[F:24][C:23]1[CH:22]=[C:21]2[C:20](=[CH:19][C:18]=1[C:16]#[N:17])[NH:25][C:9]1[C:10]([CH3:14])([CH3:13])[C:11]3[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH2:7][C:8]2=1
Reactant: N#Cc1cc(NN)ccc1F
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)c(F)cc3c1C2

Procedure:
Under the same conditions as the method for synthesizing Compound A3-1, the title compound was prepared from Compound A2 and 3-cyano-4-fluorophenylhydrazine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:5]=[C:4]([S:22][CH3:23])[N:3]=1.[C:24]([O-:27])(=[O:26])[CH3:25].[Na+].CN(C=O)C>O>[C:24]([O:27][C:2]1[C:7]([C:8](=[O:9])[NH2:10])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:5]=[C:4]([S:22][CH3:23])[N:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)[O-]
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2cnc3ccccc3c2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(Nc2cnc3ccccc3c2)c(C(N)=O)c(OC(C)=O)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 97.7 %

Procedure:
To a mixture of 4-chloro-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidine-5-carboxamide (Preparation Example 344) (0.68 g) and sodium acetate (0.80 g), DMF (7 mL) was added and stirred at 100° C. for 6 hours. After the reaction liquid was returned to room temperature, water was added, and the resulting solid was collected by filtration to give 5-carbamoyl-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidin-4-yl acetate (0.71 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[Br:5][C:6]1[CH:7]=[CH:8][C:9]([OH:26])=[C:10]([CH:25]=1)[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1)[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:26][CH2:2][CH2:3][CH3:4])=[C:10]([CH:25]=1)[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1)[CH2:13][CH3:14]
Reactant: CCCBr
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)OC)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C(=O)OC)cn1
Reaction time: 18 h
Yield: 54.5 %

Procedure:
1-Bromopropane (0.12 g, 0.69 mmol) was treated with a solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]-5-pyridylcarboxylate (0.2 g, 0.55 mmol) in DMF (4 ml). Potassium carbonate (230 mg, 1.7 mmol) was added to this solution and the reaction mixture was stirred for 18 hours. The solvent was evaporated and the residue taken up in water (4 ml) and extracted with ethyl acetate (3×3 ml). The combined extracts were evaporated and the residue subjected to chromatography (eluant: ethyl acetate/hexane) to give the title compound as a pale yellow oil (0.122 g, 54%) which was used in the subsequent step without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:22][CH:23]1[CH2:27][N:26]([CH3:28])[C:25](=[O:29])[CH2:24]1>>[CH3:28][N:26]1[C:25](=[O:29])[CH2:24][CH:23]([NH:22][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:27]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CN1CC(N)CC1=O
Agent: Cl
Product: CN1CC(NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)CC1=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 4-amino-1-methylpyrrolidin-2-one hydrochloride (CAN 1228838-07-0) as starting materials. MS (EI): m/e=381.3 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:13][CH:14]=1
Reactant: CC1NC(=O)NN=C1c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1NC(=O)NN=C1c1ccc(O)cc1
Yield: 40.3 %

Procedure:
6-(4-Benzyloxyphenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.5 g) obtained by the procedure of Examples 3-(1) to 3-(5) was dissolved in acetic acid (36 ml) and the hydrogenolysis reaction was carried out with 5% palladium on carbon (1.6 g) at atmospheric pressure and room temperature. After the theoretical amount of hydrogen gas had been absorbed, the catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure. To the residue was added water and the solid which formed was collected and recrystallized from 90% ethanol to give 6-(4-hydroxyphenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.42 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([N:36]3[CH2:41][CH2:40][N:39]([CH:42]([CH3:44])[CH3:43])[CH2:38][CH2:37]3)=[C:29]3[C:33]=2[C:32](=[O:34])[N:31]([CH3:35])[CH2:30]3)[C:21]([Cl:45])=[CH:20][N:19]=1>>[Cl:45][C:21]1[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([N:36]3[CH2:37][CH2:38][N:39]([CH:42]([CH3:44])[CH3:43])[CH2:40][CH2:41]3)=[C:29]3[C:33]=2[C:32](=[O:34])[N:31]([CH3:35])[CH2:30]3)=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CC(C)N1CCN(c2ccc(Nc3nc(Cl)ncc3Cl)c3c2CN(C)C3=O)CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCN(C(C)C)CC5)c5c4C(=O)N(C)C5)n3)cc2CC1

Procedure:
The title compound was prepared from 3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (35 mg, 0.16 mmol) and 7-(2,5-dichloropyrimidin-4-ylamino)-4-(4-isopropylpiperazin-1-yl)-2-methyl-2,3-dihydroisoindol-1-one (70 mg, 0.2 mmol) in an analogous manner to Example 946 to afford a pale yellow solid (60 mg, 60%). Mp: 190-2° C. LCMS (m/e) 619 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.60 (s, 1H), 8.63 (d, J=8 Hz, 1H), 8.09 (s, 1H), 7.39 (s, 1H), 7.29 (m, 1H), 7.10 (m, 2H), 6.92 (s, 1H), 4.39 (s, 2H), 3.60 (m, 2H), 3.40 (s, 3H), 3.23 (s, 3H), 3.15-2.86 (m, 8H), 2.84-2.60 (m, 10H), 1.82 (m, 1H), 1.12 (d, J=6 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C@@H:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@H:12]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[O:9])=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[CH3:32])=[O:9])=[CH:6][CH:7]=1
Reactant: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of the compound (1.09 g) obtained in step 2 in ethyl acetate (8 mL) was added 4N hydrogen chloride/ethyl acetate (8 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a mixture of ethyl acetate and acetonitrile. This solution was washed with 1N aqueous sodium hydroxide solution and dried, and the solvent was evaporated under reduced pressure to give 4-bromo-N-[(3R,4R)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methylbenzamide (0.830 g, 93%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[O:39])=[CH:36][N:35]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(Cl)(Cl)Cl.O.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>[C:38]([C:37]1[CH:41]=[CH:42][C:34]([C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[O:14][C:11]2([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH2:22][C:21]3=[O:23])=[N:35][CH:36]=1)(=[O:39])[NH2:40]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1O2
Reactant: NC(=O)c1ccc(Cl)nc1
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: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3ccc(C(N)=O)cn3)ccc1O2
Temperature: 100 °C

Procedure:
1′-tert-butoxycarbonyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[chroman-2,4′-piperidin]-4-one (40.0 g, 90.0 mmol), 6-chloronicotinamide (17.0 g, 108 mmol), Pd(PPh3)4 (5.21 g, 4.51 mmol), and aqueous 2M Na2CO3 (100 ml) solution were suspended in dioxane (300 ml) and heated at 100° C. for 16 h. The reaction mixture was diluted with CHCl3 and H2O, the aqueous layer was extracted with CHCl3. The combined organic layer was washed with brine, dried over MgSO4 and silicagel. The desiccant was removed through celite filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by crystallization (CHCl3-EtOAc) to obtain the intended compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:13]([CH:14]3[CH2:17][N:16]([CH:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15]3)[N:12]=[CH:11][CH:10]=2)[CH:3]=1.[C:31]([C:33]1[CH:34]=[C:35]([S:40]([N:43]([C:51]2[N:52]=[CH:53][S:54][CH:55]=2)[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1F)#[N:32].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:38]2[CH:37]=[CH:36][C:35]([S:40]([N:43]([C:51]3[N:52]=[CH:53][S:54][CH:55]=3)[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:42])=[O:41])=[CH:34][C:33]=2[C:31]#[N:32])=[C:4]([C:9]2[N:13]([CH:14]3[CH2:17][N:16]([CH:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15]3)[N:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Oc1ccc(Cl)cc1-c1ccnn1C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(Oc2ccc(Cl)cc2-c2ccnn2C2CN(C(c3ccccc3)c3ccccc3)C2)c(C#N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenol, (Preparation 689, 75 mg, 0.18 mmol), tert-butyl [(3-cyano-4-fluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 250, 69 mg, 0.18 mmol), potassium carbonate (62 mg, 0.45 mmol) and dimethyl sulphoxide (4 ml) were combined and stirred at room temperature under nitrogen for 4 hours. Saturated aqueous ammonium chloride solution (20 ml) was added and the mixture extracted with ethyl acetate (1×20 ml). The organic layer was separated and back-washed with saturated aqueous sodium chloride solution (2×20 ml). The organic layer was separated, dried over sodium sulphate, filtered and evaporated to give an oil. The oil was purified using an ISCO® Companion (4 g. silica gel, gradient from dichloromethane to dichloromethane:methanol 98:2). The appropriate fractions were combined and solvents removed in vacuo to give the title compound as a glass. Yield 33 mg. 24%.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CC1C=CC(S(O[CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)(=O)=O)=CC=1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:12][CH2:11]1
Reactant: COc1ccc(CCN2CCNCC2)cc1OC
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: COc1ccc(CCN2CCN(CCOc3ccc(Cl)cc3)CC2)cc1OC

Procedure:
To the solution of 1-(3,4-dimethoxyphenethyl)piperazine dihydrochloride (502 mg, 1.55 mmol) and 2-(4-chlorophenoxy)ethyl 4-methylbenzenesulfonate (460 mg, 1.4 mmol) in acetone (20 mL) was added NaI (465 mg, 3.1 mmol) and K2CO3 (1.1 g, 7.0 mmol). The reaction mixture was then refluxed overnight and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by column chromatography to afford 1-(3,4-dimethoxyphenethyl)-4-(2-(4-chlorophenoxy)ethyl)piperazine which was suspended in 6 N HCl(aq). (pH=3). The precipitate was filtered, washed with cold ethanol, and dried to afford the title compound (350 mg, 52%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)=[CH:4][CH:3]=1.C1(C)C=CC([S:21]([N:24]=[N+:25]=[N-])(=O)=O)=CC=1.C(N(CC)CC)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCCC1.O.C(#N)C>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[S:21][N:24]=[N:25][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1nnsc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A mixture of methyl 4-fluorobenzoylacetate (3.92 g), p-toluenesulfonyl azide (4.00 g), triethylamine (2.02 g) and acetonitrile (30 ml) was stirred at 0° C. for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give a yellow oil. The Lawesson's reagent (8.10 g) and tetrahydrofuran (50 ml) were added to this yellow oil and the mixture was heated under reflux for 16 hrs. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to give methyl 5-(4-fluorophenyl)-1,2,3-thiadiazole-4-carboxylate (1.95 g, yield 41%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:34])(=[O:33])[CH:30]([CH3:32])[OH:31]>C(O)(C)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:34])(=[O:33])[CH:30]([CH3:32])[OH:31]
Reactant: CC(O)C(=O)O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(C)O
Product: CC(O)C(=O)[O-]
Temperature: 80 °C
Reaction time: 8.5 h

Procedure:
Sitagliptin (5 g) and isopropanol (75 mL) are charged into a round-bottom flask and the mixture is heated to about 80° C. for about 20 minutes to obtain a clear dissolution. Lactic acid (1.10 g) is added and the reaction mixture is refluxed for about 1.5 hours. The reaction mixture is cooled to about 30° C. and stirred for about 8.5 hours. The separated solid is filtered, washed with isopropanol (5 mL), and dried under reduced pressure at about 45° C. for about 2 hours to afford the title compound. (Yield: 4.0 g; MC: 0.62% w/w; HPLC purity: 99.75%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=[O:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]([CH:19]([CH3:21])[CH3:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:15])=[C:12]([CH:16]([CH3:17])[CH3:18])[N:11]([CH:19]([CH3:21])[CH3:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C=O)c(OCc2ccccc2)nn1C(C)C
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1c(C(O)c2ccccc2)c(OCc2ccccc2)nn1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzyloxy-4-formyl-1,5-diisopropyl-1H-pyrazole (0.21 g) in tetrahydrofuran (10 mL) was added a solution of phenylmagnesium bromide in tetrahydrofuran (1 mol/L, 1.5 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. A saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was purified by column chromatography on aminopropylated silica gel (eluent:tetrahydrofuran). Further purification by column chromatography on silica gel (eluent:hexane/ethyl acetate=10/1-2/1) to give the adduct material, [3-benzyloxy-1,5-diisopropyl-1H-pyrazole-4-yl] phenyl methanol. The obtained adduct material was dissolved in ethanol, and a catalytic amount of 10% palladium-carbon powder was added to the solution. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (0.16 g).