Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]2[CH:15]=[CH:16][S:17][C:3]=12.[NH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[NH:23]1[CH2:24][CH2:25][CH:20]([CH2:19][NH:18][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[N:5]=[C:4]3[CH:15]=[CH:16][S:17][C:3]=23)[CH2:21][CH2:22]1
Reactant: Fc1ccc(-c2cc(Cl)c3sccc3n2)cc1
Reactant: NCC1CCNCC1
Product: Fc1ccc(-c2cc(NCC3CCNCC3)c3sccc3n2)cc1
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (60 mg, 0.23 mmole) in 4-aminomethylpiperidine (1 mL) is heated at 160°C. oil bath under N2 for 4 hours. The reaction mixture is cooled to room temperature and purified on preperative tlc plate to give N-(4-piperidinylmethyl)-5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-amine (15 mg, 19% yield) as a colorless oil. This material is dissolved in 1 mL ethyl acetate. Ethyl acetate saturated with HCl (2 mL) is added and then concentrated to afford N-(4-piperidinylmethyl)-5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-amine dihydrochloride (compound 1) as a greasy oil. The salt is triturated with ether, collected by filtration, washed with ether and dried in vacuo, m.p. >260° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:16])[CH:9]=2)=[CH:4][CH:3]=1.Cl[C:29]1[C:34]([I:35])=[CH:33][N:32]=[CH:31][N:30]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>>[I:35][C:34]1[C:29]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=4)=[O:16])[CH:9]=3)=[CH:4][CH:3]=2)=[N:30][CH:31]=[N:32][CH:33]=1
Reactant: Clc1ncncc1I
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1ccc(Nc2ncncc2I)cc1
Yield: 44.3 %

Procedure:
4′-Amino-6-methyl-N-[3-(trifluoromethyl)phenyl]biphenyl-3-carboxamide (0.26 g, 0.00070 mol) was mixed with 4-chloro-5-iodopyrimidine (0.17 g, 0.00070 mol) in ethanol (3.00 mL, 0.0514 mol) and the mixture was heated to reflux for 2 hours at which time LCMS analysis showed mainly product. To the reaction was added sat. Na2CO3 solution and the mixture was extracted with ethyl acetate. The organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 30% EtOAc/hexanes to give the product (178 mg, 44% yield). 1H NMR (CDCl3): 8.66 (s, 1H), 8.62 (s, 1H), 7.96 (m, 2H), 7.70-7.89 (m, 5H), 7.37-7.50 (m, 5H), 7.20 (s, 1H), 2.38 (s, 3H). MS (EI) m/z=575 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:6]=1[C:17]1[C:18]([O:23]CC2C=CC=CC=2)=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:2]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:6]=1[C:17]1[C:18](=[O:23])[NH:19][CH:20]=[CH:21][CH:22]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1ccc[nH]c1=O
Reaction time: 2 h

Procedure:
step 2—To a solution of 78 (109 mg, 0.26 mmol) in MeOH (7 mL) and THF (1 mL) was added 20% Pd(OH)2/C (wet, 20 mg). The reaction mixture was stirred under an atmosphere of hydrogen (balloon) for 2 h then filtered through a pad of CELITE, rinsing with EtOAc. The filtrate was concentrated under reduced pressure to afford 79 mg (93%) of I-54 as an off-white solid: MS=330 [M+H]+.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.C(O[C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34]#[N:35])=[CH:31][CH:32]=2)[NH:27][C:26]=1[C:36]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([Br:47])[CH:40]=1)([CH3:38])[CH3:37])=[O:24])C.O>CC#N>[Br:47][C:41]1[C:42]([O:45][CH3:46])=[CH:43][C:44]2[C:23](=[O:24])[C:25]3[C:33]4[C:28](=[CH:29][C:30]([C:34]#[N:35])=[CH:31][CH:32]=4)[NH:27][C:26]=3[C:36]([CH3:38])([CH3:37])[C:39]=2[CH:40]=1
Reactant: CCOC(=O)c1c(C(C)(C)c2ccc(OC)c(Br)c2)[nH]c2cc(C#N)ccc12
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC#N
Solvent: O
Product: COc1cc2c(cc1Br)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
Phosphorus pentoxide-methanesulfonic acid (12 mL) was added with 2-[1-(3-bromo-4-methoxy-phenyl)-1-methyl-ethyl]-6-cyano-1H-indole-3-carboxylic acid ethyl ester (Compound K5, 1.0 g, 2.27 mmol), and the mixture was stirred at room temperature for 20 min. The reaction solution was diluted with MeCN (20 mL), poured into water (20 mL), and the precipitated solid was filtered to obtain the title compound (yellow solid, 763 mg, 85%).
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[C:24]1([CH2:30][CH:31]([NH2:37])[C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:30][CH:31]([NH:37][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])[C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: NC(Cc1ccccc1)c1cccs1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(Cc1ccccc1)c1cccs1
Yield: 45 %

Procedure:
The title compound was prepared in a yield of 45% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 2-phenyl-1-(2-thienyl)ethylamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]#[N:7])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[N:8]=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:27][C:6]=1[NH2:7])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(C#N)NC(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2ccccc2)sc1N
Temperature: 100 °C
Reaction time: 120 h

Procedure:
A solution of benzoylamino-cyano-acetic acid ethyl ester (400 mg, 1.7 mmol) in toluene (4 ml) was flushed with argon, and Lawesson's reagent (314 mg, 0.85 mmol) was added. The reaction mixture was stirred at 100° C. for 5 days. The solvent was evaporated, and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as yellow solid (147 mg, 34%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:31]([Cu])#[N:32].[OH-].[NH4+].Cl>CCOC(C)=O.CN1CCCC1=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:31]#[N:32])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Temperature: 120 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A mixture of 1-bromo-4-hydroxy-6-(4-propoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (315 mg, 0.664 mmol), CuCN (66 mg, 0.730 mmol), and N-methylpyrrolidinone (2 mL) was stirred at 120° C. for 4 h. After cooling to room temperature the mixture was poured into EtOAc (20 mL) and saturated ammonium hydroxide solution (˜1 mL) was added. The mixture was rapidly stirred for 2 min. Then it was acidified with concentrated HCl, washed with water, and saturated NaCl solution before it was dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography to give title compound (206 mg). ESI MS (m/z): 421 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:49]([O:56][C:57]1[CH:81]=[CH:80][C:79](O)=[CH:78][C:58]=1[C:59]([NH:61][C:62]1[CH:71]=[C:70]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH:69]=[CH:68][C:63]=1[C:64]([O:66][CH3:67])=[O:65])=[O:60])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O1CCCC1>[CH2:49]([O:56][C:57]1[CH:81]=[CH:80][C:79]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[CH:78][C:58]=1[C:59]([NH:61][C:62]1[CH:71]=[C:70]([C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)[CH:69]=[CH:68][C:63]=1[C:64]([O:66][CH3:67])=[O:65])=[O:60])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(O)ccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.26 g), triphenylphosphine (0.35 g), and diisopropyl azodicarboxylate (0.26 mL) were added to a tetrahydrofuran (5.0 mL) solution of methyl 2-(2-(benzyloxy)-5-hydroxybenzamido)-4-phenylbenzoate (0.50 g), followed by stirring at room temperature for 30 minutes. Triphenylphosphine (0.35 g) and diisopropyl azodicarboxylate (0.26 mL) were added to the reaction mixture, followed by stirring at room temperature for 30 minutes. Triphenylphosphine (0.35 g) and diisopropyl azodicarboxylate (0.26 mL) were added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 95-70% hexane/ethyl acetate] to obtain methyl 2-(2-(benzyloxy)-5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)benzamido)-4-phenylbenzoate as a yellow oily substance.
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[C:37]4[C:32](=[C:33]([Cl:38])[CH:34]=[CH:35][CH:36]=4)[N:31]=[N:30][C:29]=3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:23]=2)[CH:15]=1>C1(C)C=CC=CC=1>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:32]=1[N:31]=[N:30][C:29]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[C:28]2[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:12])[CH:15]=2)[CH:23]=1
Reactant: COC(=O)c1cccc(COc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1
Reactant: C1COCCN1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(c1cccc(COc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1)N1CCOCC1
Temperature: 60 °C

Procedure:
A solution of trimethylaluminum (2 M solution in dichloromethane, 0.5 M) was added to a solution of morpholine (0.1 g) in 5 mL of toluene at room temperature. After 30 minutes 3-[3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenoxymethyl]-benzoic acid methyl ester (50 mg) in 2 mL of toluene was added and the solution was heated to 60° C. for 15 hours. The reaction mixture was cooled to room temperature, quenched with diluted HCl and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by semi-preparative HPLC. MS (ES) m/z 536.2.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]2[CH2:11][CH2:10][CH2:9][S:8][C:7]=12.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][CH2:21][N:4]1[C:3](=[O:13])[C:2]([CH3:1])=[C:7]2[S:8][CH2:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:12]
Reactant: Cc1c2n(c(=O)[nH]c1=O)CCCS2
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c2n(c(=O)n(CCCCCl)c1=O)CCCS2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 3.28 g (16.5 mmol) of 9-methyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 3.81 g (28.8 mmol) of potassium carbonate in 70 ml of N,N-dimethylformamide, 2.07 ml (36 mmol) of 1-bromo-4-chlorobutane was added at room temperature, followed by stirring at 60° C. for 2 hours and then at 100° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane-water; the organic layer was washed with water and dried. The oily substance obtained by distilling off the solvent was purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1-2/1) to yield 3.24 g (67.9%, light yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH:9]=O)=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[NH2:18].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:23][O:22][C:20]1[CH:19]=[C:17]([NH:18][CH2:9][C:8]2[C:3]([NH:2][CH3:1])=[N:4][C:5]([S:11][CH3:12])=[N:6][CH:7]=2)[CH:16]=[C:15]([O:14][CH3:13])[CH:21]=1
Reactant: CNc1nc(SC)ncc1C=O
Reactant: COc1cc(N)cc(OC)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNc1nc(SC)ncc1CNc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (1.0 g, 5.46 mmol) and 3,5-dimethoxyaniline (840 mg, 5.46 mmol) in methanol (60 mL) was stirred at RT for 3 h, followed by the addition of sodium cyanoborohydride (520 mg, 8.20 mmol) and 1 mL of acetic acid. The reaction mixture was then stirred at RT for another 4 h. LCMS showed the reaction was completed. The reaction was quenched by 30 mL of 1N HCl, then stirred for 0.5 h and extracted with ethyl acetate (3×50 mL). The organic layers were separated, combined, washed with saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (crude 1.2 g, 69%) as a white solid, which was directly used in the next step without further purification. MS (ES+) C15H20N4O2S requires: 320. found: 321 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:18].[C:19]([Cu])#[N:20]>CN1C(=O)CCC1>[Cl:18][C:3]1[C:4]2[N:8]=[C:7]([CH2:9][CH3:10])[N:6]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:5]=2[CH:16]=[CH:17][C:2]=1[C:19]#[N:20]
Reactant: N#C[Cu]
Reactant: CCc1nc2c(Cl)c(Br)ccc2n1CC(F)(F)F
Solvent: CN1CCCC1=O
Product: CCc1nc2c(Cl)c(C#N)ccc2n1CC(F)(F)F
Temperature: 220 °C
Yield: 49.2 %

Procedure:
5-Bromo-4-chloro-2-ethyl-1-(2,2,2-trifluoroethyl)-1H-benzimidazole (0.036 g, 0.106 mmol) and CuCN (0.020 g, 0.222 mmol) were combined in NMP (3 mL) and heated to 220° C. for 20 min in a microwave. The cooled mixture was partitioned between Et2O and water, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.015 g): 1NMR (400 MHz, CDCl3) δ 7.56 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.68 (q, J=8.2 Hz, 2H), 2.96 (q, J=7.4 Hz, 2H), 1.45 (t, J=7.4 Hz, 3H); MS (ESI) m/z 288 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C[Mg]Br.[O:12]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]3[O:27][C:26](=[O:28])[C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[N:23]=3)[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[NH:23][C:22]([N:19]2[CH2:18][CH2:17][C:16]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:21][CH2:20]2)=[O:27])=[N:3][CH:4]=1
Reactant: O=c1oc(N2CCC3(CC2)OCCO3)nc2ccccc12
Reactant: Nc1ccc(Cl)cn1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)N1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-amino-5-chloropyridine (573 mg, 4.51 mmol) in tetrahydrofuran (25 mL) at 0° C. under nitrogen was added methylmagnesium bromide (3.0 M in ether, 1.50 mL, 4.51 mmol) dropwise via a syringe. After stirring at 0° C. for 10 min, 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4H-3,1-benzoxazin-4-one (1.30 g, 4.51 mmol) was added. After stirring 15 h at room temperature, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium chloride and the layers separated. The organic phase was washed with water, dried (magnesium sulfate), filtered, and concentrated in vacuo to give, after recrystallization from EtOAc, 880 mg (47%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=O)[CH:4]=[N:3]1.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:38]=[CH:37][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:38]=[CH:37][C:19]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: Cc1c(C=O)cnn1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1c(CN2CCC(c3ccc(C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)cc3)CC2)cnn1C
Reaction time: 2.5 h
Yield: 83.8 %

Procedure:
1,5-Dimethyl-1H-pyrazole-4-carbaldehyde (114 mg, 0.92 mmol) was added to a solution of tert-butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (289 mg, 0.73 mmol) in dichloromethane (6 ml) followed by acetic acid (50 μl, 0.87 mmol). The reaction mixture was allowed to stir under nitrogen for 2.5 hours. Sodium triacetoxyborohydride (233 mg, 1.10 mmol) was added and the reaction mixture allowed to stir, at ambient temperature, for 18 hours (overnight). Saturated aqueous sodium bicarbonate solution (10 ml) was then added to the reaction and allowed to stir for 15 minutes. The organic phase was separated and the aqueous phase re-extracted with dichloromethane (10 ml). The combined organics were washed with water, dried over magnesium sulphate and evaporated to dryness to afford the product as a colourless gum (308 mg, 84%), which was used without further purification; Mass Spectrum: M+H+504.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]3[CH:16]=[CH:17][O:18][C:14]=3[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)(=O)C>Cl>[NH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[C:15]3[CH:16]=[CH:17][O:18][C:14]=3[CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:9]1
Reactant: CC(=O)N1CCC(c2nccc3occc23)CC1
Agent: Cl
Product: c1cc2occc2c(C2CCNCC2)n1

Procedure:
A solution of 2.7 g of the product obtained in Step D in 80 ml of HCl (4N) is heated at 100° C. for 12 hours and then cooled, washed with ether, and rendered basic to a pH of 10 by the addition of an aqueous sodium hydroxide solution. After extraction with dichloromethane, the organic phase is dried, filtered and then evaporated to dryness enabling the expected product to be obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]=[O:20])[CH2:15][CH2:14]1>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([CH:19]=[O:20])[CH2:17][CH2:18]2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=CN1CCC(CCCBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1CCCC1CCN(C=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A mixture of 2-methylimidazole (2 g, 0.025 M) and sodium hydride (1.2 g, 50% in mineral oil, 0.025 M) in dimethylformamide (20 ml) was stirred at room temperature for 1/2 hr. The reaction mixture was then heated at 50° C. and the solution of 4(3-bromopropyl)piperidine carboxaldehyde (4.6 g, 0.02 M) in dimethylformamide (20 ml) was added slowly. After completing the addition, the reaction was heated at 50° C. for 4 hrs and then solvent was removed in vacuo. Water (80 ml) was added to the residue and the mixture was extracted with methylene chloride. The combined extracts, dried over sodium sulfate, were stripped to dryness to yield an oil. The oil was purified on silica gel column, eluted with methanol chloroform (1:9 v/v) to give 4-[3-(2-methyl-1H-imidazol-1-yl)-propyl]-1-piperidinecarboxaldehyde (3.86 g, 88% yield).
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[CH2:29][OH:30])=[O:23])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[CH2:29][O:30][C:38](=[O:40])[CH3:39])=[O:23])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2CO)n2c1COCC2)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2COC(C)=O)n2c1COCC2)c1ccccc1
Yield: 55 %

Procedure:
A mixture of 6-((R)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 16ei) (0.213 mmol), triethylamine (31 mg, 0.31 mmol), acetyl chloride (24 mg, 0.31 mmol) and 4-dimethylamino-pyridine (ca. 1 mg) in dry dichloromethane was stirred overnight. After addition of aqueous sodium hydrogencarbonate, extraction (3 times with dichloromethane), and drying of the combined organic layers over sodium sulfate, the solvents were evaporated and the residue was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give acetic acid (R)-1-[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidin-2-ylmethyl ester (54 mg, 55%). LC/MS (method 4): Rt=1.23 min; m/z=454.31 (M+H+).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:10][CH:9]1[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[C:13]([C:22]2[CH:31]=[C:30]3[C:25]([C:26]([CH3:36])([CH3:35])[CH2:27][C:28](=[O:34])[N:29]3[CH2:32][CH3:33])=[CH:24][C:23]=2[CH3:37])[CH:12]=1)=[O:7])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:32]([N:29]1[C:30]2[C:25](=[CH:24][C:23]([CH3:37])=[C:22]([C:13]3[CH:12]=[C:11]([CH:9]4[CH2:10][CH:8]4[C:6]([OH:7])=[O:5])[CH:16]=[CH:15][C:14]=3[O:17][C:18]([F:20])([F:19])[F:21])[CH:31]=2)[C:26]([CH3:36])([CH3:35])[CH2:27][C:28]1=[O:34])[CH3:33]
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C4CC4C(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C4CC4C(=O)O)ccc3OC(F)(F)F)cc21

Procedure:
A solution of Compound 40A in CH2Cl2 (2 mL) and TFA (1 mL) was stirred at r.t. overnight after which the solvent was removed in vacuo to obtain the desired product (Compound 40) as pale yellow powder (0.036 g). The compound is racemic (i.e. mixture of both enantiomers). The designated “trans” stereochemistry merely describes the relative stereochemistry for the two substituents on the cyclopropane ring. MS (electrospray): mass calculated for C25H26F3NO4, 461.18; m/z found 462 [M+H]+.