Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([C:18]3[N:22]4[CH:23]=[C:24]([C@@H:27]([N:32]5[CH2:36][CH2:35][C@H:34]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]5)[C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=3)=[N:15]2)=[CH:10][C:9]=1[F:45])(=O)C.[Li+].[OH-]>CO>[F:31][C:28]([F:29])([F:30])[C@H:27]([N:32]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:39])[O:40][C:41]([CH3:44])([CH3:42])[CH3:43])[CH2:33]1)[C:24]1[CH:25]=[CH:26][C:21]2[N:22]([C:18]([C:14]3[CH:13]=[CH:12][C:11]4[C:16](=[CH:17][C:8]([O:7][CH2:6][CH2:5][OH:4])=[C:9]([F:45])[CH:10]=4)[N:15]=3)=[N:19][N:20]=2)[CH:23]=1
Reactant: CC(=O)OCCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To 2-(2-(6-((R)-1-((S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro quinolin-7-yloxy)ethyl acetate (250 mg, 0.395 mmol) (Example 122, Step A) in MeOH (5 mL) was added 2N LiOH (1 mL) and the reaction was stirred at ambient temperature for 1 hour. The reaction was concentrated and the residue purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 25 column volumes) to yield tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (210 mg, 90.0% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][NH2:20])[CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:54][C:55]1[CH:63]=[CH:62][C:58]([C:59](O)=[O:60])=[CH:57][CH:56]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([CH2:19][NH:20][C:59](=[O:60])[C:58]2[CH:62]=[CH:63][C:55]([F:54])=[CH:56][CH:57]=2)[CH2:17][CH2:18]1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: NC[C@H]1CC[C@H](Oc2ccnc3c(F)cccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC[C@H]1CC[C@H](Oc2ccnc3c(F)cccc23)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{trans-4-[(8-Fluoroquinolin-4-yl)oxy]cyclohexyl}methylamine (1.82 g mg, 6.63 mmol) was dissolved in tetrahydrofuran (415 mL). After adding HATU (2.78 g, 7.30 mmol), diisopropylethylamine (1.30 mL, 7.30 mmol) and 4-fluorobenzoic acid (1.02 g, 7.30 mmol), the reaction mixture was stirred overnight at room temperature. After chromatography, the desired product was obtained at 71% yield (1.96 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]3[O:17][C:18]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH:29]=O)[CH:25]=5)[C:19]=4[N:20]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:31]1[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]1.C([BH3-])#N.[Na+].CO.ClCCl>ClC(Cl)C.CO.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]3[O:17][C:18]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH2:29][N:31]6[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]6)[CH:25]=5)[C:19]=4[N:20]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2c(ccc3oc(CCC4(c5ccc(F)cc5)CCCCC4)nc32)c1
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CO
Product: O=C(O)C1CN(Cc2ccc3c(ccc4oc(CCC5(c6ccc(F)cc6)CCCCC5)nc43)c2)C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)naphtho[1,2-d]oxazole-7-carbaldehyde (Preparation 42E, 47.0 mg, 0.117 mmol) in dichloroethane (1 mL) and methanol (1 mL) was added azetidine-3-carboxylic acid (23.66 mg, 0.234 mmol) followed by 2 drops of acetic acid. Next, the reaction mixture was stirred in a 60° C. in an oil bath for 1 hr. After cooling to room temp sodium cyanoborohydride (14.71 mg, 0.234 mmol) was added, and the mixture was stirred at room temperature overnight. Next, the reaction mixture was placed on a Combiflash column (12 g silica gel) filled with 7:93 methanol-dichloromethane, and eluted with 2:8 followed by 3:7 and 1:1 MeOH—CH2Cl2 to give the 1-((2-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)naphtho[1,2-d]oxazol-7-yl)methyl)azetidine-3-carboxylic acid as a brown solid. LC/MS M+1=487.31; 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (1H, d, J=8.36 Hz), 7.81 (1H, s), 7.58 (1H, d, J=9.02 Hz), 7.50 (1H, d, J=8.80 Hz), 7.46 (1H, d, J=9.02 Hz), 7.24-7.31 (2H, m), 6.98 (2H, t, J=8.69 Hz), 4.03 (2H, br. s.), 3.79-3.96 (4H, m), 3.31 (1H, br. s.), 2.51-2.60 (2H, m), 2.00-2.14 (4H, m), 1.29-1.65 (8H, m).
Reaction SMILES: [C:1]([C:3](=[C:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:4](Cl)=[O:5])#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.OS(O)(=O)=O>[C:1]([C:3](=[C:7]([C:8]1[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=1)[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:4][OH:5])#[N:2]
Reactant: N#CC(C(=O)Cl)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: N#CC(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 69.4 %

Procedure:
The acyl chloride prepared in Step A was dissolved in 40 mL of tetrahydrofuran and was chilled to -78° C. under an inert atmosphere. To this pale greenish solution at -78° C. was added 10 mL lithium aluminum hydride in tetrahydrofuran solution (1 M, 10 mmol). Reduction was allowed to proceed at -78° C. for 20 minutes before it was diluted with H2SO4 dilute solution (2 M, 20 mL). The desired product was extracted twice into ethyl acetate (40 mL×2). Organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to give 2.64 g (69.4%) of the title compound. The crude allylic alcohol was used in the next step without further purification. An analytically pure sample was prepared by crystallization from a mixture of ethyl acetate-hexanes (1:9, v/v) m.p.=110°-112° C.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH3:28]>C(#N)C>[CH2:25]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=2[F:1])[CH2:13][CH2:14]1)[CH2:26][CH2:27][CH3:28]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)-phenyl]-piperidine (0.02 g, 0.078 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 1-bromobutane (0.009 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 313 (M+, 2), 271 (14), 270 (bp), 147 (7) 133 (7).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[CH3:66][N:67]1[CH2:71][CH2:70][CH2:69][CH:68]1[CH2:72][CH2:73][NH2:74]>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:74][CH2:73][CH2:72][CH:68]5[CH2:69][CH2:70][CH2:71][N:67]5[CH3:66])=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCCC1CCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCC2CCCN2C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 82.5 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.015 g (0.12 mmole) 2-(1-methyl-pyrrolidin-2-yl)-ethylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.046 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-benzamide (I-112) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[CH:18]=2)[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:21]1([C:19]([C:17]2[CH:18]=[C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[S:15][CH:16]=2)=[O:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(C(=O)N3CCCCCC3)cs2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1csc(C2CCCNC2)c1)N1CCCCCC1
Reaction time: 1 h
Yield: 105.8 %

Procedure:
3-[4-(Azepane-1-carbonyl)-thiophen-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.066 g) was dissolved in TFA/DCM (1:1, 5 mL) and stirred for 1 hour. The solvent was then evaporated and the residue dissolved in DCM and purified using a SCX-2 column. After washing with methanol and acetonitrile, the desired compound was washed from the column with ammonia (2 M in MeOH). Evaporation gave the title compound as a clear colourless oil (0.052 g). LCMS m/z 293.14 [M+H]+ RT=5.27min (Analytical Method 2). 1H NMR δ (ppm)(CHCl3-d): 7.3 (s, 1H), 6.9 (s, 1H), 3.8 (m, 2H), 3.5 (m, 2H), 3.3 (d, 1H), 3.1 (d, 1H), 2.9 (m, 1H), 2.7-2.6 (m, 3H), 2.1 (m, 1H), 1.8-1.5 (m, 11H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[C:13]2[CH:14]=[CH:15][C:16]([Br:18])=[CH:17][C:12]=2[CH2:11][CH2:10][O:9]1)(=O)=O.[C:19]([C:21]1[CH:36]=[CH:35][C:24]2[C:25]([N:28]3[CH2:33][CH2:32][NH:31][C@H:30]([CH3:34])[CH2:29]3)=[CH:26][S:27][C:23]=2[CH:22]=1)#[N:20]>>[Br:18][C:16]1[CH:15]=[CH:14][C:13]2[C@H:8]([CH2:7][CH2:6][N:31]3[CH2:32][CH2:33][N:28]([C:25]4[C:24]5[CH:35]=[CH:36][C:21]([C:19]#[N:20])=[CH:22][C:23]=5[S:27][CH:26]=4)[CH2:29][C@H:30]3[CH3:34])[O:9][CH2:10][CH2:11][C:12]=2[CH:17]=1
Reactant: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(Br)ccc21
Product: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1CC[C@@H]1OCCc2cc(Br)ccc21

Procedure:
The title compound was prepared from 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethyl methanesulfonate and (3R)-1-(6-cyano-1-benzothien-3-yl)-3-methylpiperazine, as described for Example 1b).
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7]OS(C)(=O)=O)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.[CH3:17][NH:18][CH3:19]>>[S:1]1[C:5]([CH2:6][CH2:7][N:18]([CH3:19])[CH3:17])=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: CNC
Reactant: CS(=O)(=O)OCCc1cc2ccccc2s1
Product: CN(C)CCc1cc2ccccc2s1
Temperature: 80 °C
Yield: 94 %

Procedure:
To methanesulfonic acid 2-benzo[b]thiophen-2-yl-ethyl ester (2.93 mmol) was added dimethylamine (30 mL, 2M in EtOH) and the mixture was heated in a sealed flask for 2 hrs at 80° C. Monitoring by TLC indicated complete conversion and the mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with sat. NaHCO3 (2×) and subsequently extracted with 1N HCl (3×). The combined HCl layers were made basic with sat. NaHCO3, extracted with EtOAc (4×) and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give Compound 1a (2-Benzo[b]thiophen-2-yl-ethyl)-dimethyl-amine (561 mg, 94%) as a tan solid; MS(MH+)=206.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][C:29](O)=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1.O1CCCC1.C([N:42](CC)C(C)C)(C)C.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[F:32][C:2]([F:1])([F:33])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][C:29]([NH2:42])=[O:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1
Reactant: O=C(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Product: NC(=O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a round bottom flask containing (4-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-acetic acid (0.150 g, 0.000315 mol) in tetrahydrofuran (2.0 mL, 0.025 mol) was added N,N-diisopropylethylamine (0.33 mL, 0.0019 mol), ammonium chloride (0.10 g, 0.0019 mol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) (0.24 g, 0.00063 mol). The reaction was stirred at room temperature overnight. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The organic phases were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to yield 240 (31.5 mg) as a colorless solid. MS (ESI+) 476.1.
Reaction SMILES: [CH2:1]([P:5]([O:10][CH2:11][CH3:12])(=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH:3][CH3:4].O1CCCC1.C([Li])CCC.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>Cl.CCCCCC>[CH2:23]([CH:1]([P:5]([O:6][CH2:7][CH3:8])(=[O:9])[O:10][CH2:11][CH3:12])[CH:2]=[CH:3][CH3:4])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: CC=CCP(=O)(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC=CC(Cc1ccccc1)P(=O)(OCC)OCC
Temperature: -70 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
1.92 g of diethyl 2-butenephosphonate was placed in 10 ml. of dry tetrahydrofuran, and the solution was cooled to -70° C. in an atmosphere of argon. 7 ml. of n-butyl lithium (as a 15% by weight n-hexane solution) was gradually added, and the mixture was stirred at -70° C. for 1 hour. The reaction mixture was turbid assuming a pale yellow color. When 1.7 g of benzyl chloride was added to this mixture, it became clear. The temperature of the reaction mixture was gradually elevated to room temperature, and it was stirred for an additional 2 hours. The reaction mixture was then diluted with dilute hydrochloric acid, and extracted with ether. The extract was washed with a solution of sodium hydrogen carbonate, washed with water, and dried. The solution was concentrated, and then the residue was distilled at reduced pressure to afford 2.33 g of diethyl 1-benzyl-2-butenephosphonate having a boiling point of 144° C. (0.3 mmHg) in a yield of 93%. The analysis values of the product were as follows:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[S:13][C:14]([CH3:16])=[CH:15][C:3]=12.[OH-].[K+].[CH2:19](I)[CH3:20].Cl>O.C(O)C>[CH2:19]([N:5]1[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:2](=[O:1])[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]1=2)[CH3:20]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2sc(C)cc2c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(C)sc21

Procedure:
A mixture of 1.4 parts of ethyl 4-hydroxy-2-methylthieno-[2,3-b]pyridine-5-carboxylate, 12 parts by volume of 10 % aqueous potassium hydroxide, 48 parts by volume of ethanol, 60 parts by volume of water and 1.8 parts by volume of ethyl iodide is refluxed for about 3 hours. After cooling, the reaction mixture is added to 60 parts by volume of water containing 3 parts by volume of concentrated hydrochloric acid and the resulting crystals are collected by filtration to give 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylic acid as colorless crystals. Recrystallization from chloroform-ethanol yields colorless prisms melting at 229°-230°C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:27][C:28]1[C:29]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:30][CH:31]=[CH:32][CH:33]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:37]3[CH2:38][CH2:39][N:34]([C:29]4[C:28]([Cl:27])=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:35][CH2:36]3)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl
Reactant: Clc1cccnc1N1CCNCC1
Agent: Cl
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl)N1CCN(c2ncccc2Cl)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid (example 49, step 2) was coupled with 1-(3-chloro-pyridin-2-yl)-piperazine hydrochloride (CAS 85386-86-3) to give the title compound as a colorless solid. MS: 560.2 ([M+H]+)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[N:9]=1)[C:5]#[N:6].CN1C(=O)CCC1.[F:18][C:19]1[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=1>CCOC(C)=O>[Cl:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([NH:26][CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[CH:20]=2)[N:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: NCc1cccc(F)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)nc(NCc2cccc(F)c2)c1
Temperature: 110 °C
Yield: 99.2 %

Procedure:
To a scintillation vial containing 2,6-dichloroisonicotinonitrile (500 mg, 2.89 mmol) was added NMP (6 ml) and (3-fluorophenyl)methanamine (868 mg, 6.94 mmol). The homogenous reaction mixture was capped and heated to 110° C. in a oil bath for 1 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3, H2O and sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography on silica gel (0-20% EtOAc/Hexane) to give 2-chloro-6-(3-fluorobenzylamino)isonicotinonitrile (750 mg, 95%). LCMS (m/z): 262.0 (MH+), retention time=1.03 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:8]2([CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][CH2:13]3)[CH2:9]2)[CH2:7]1)=[O:5])[CH3:2].Cl.[CH3:24][C:25]1([NH2:29])[CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][C:25]1([NH:29][C:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH:10]3[CH2:11][C:8]4([CH2:21][CH2:22][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]4)[CH2:9]3)[CH2:13][CH2:14]2)=[O:19])[CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)N1CCC2(CC(N3CCC(C(=O)O)CC3)C2)C1
Reactant: CC1(N)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC2(CC(N3CCC(C(=O)NC4(C)CCC4)CC3)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
1-[6-(Ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid (0.368 g, 1.10 mmol) was dissolved in DMF (8 mL) and (1-methylcyclobutyl)amine hydrochloride (0.200 g, 1.64 mmol), HATU (0.458 g, 1.21 mmol) and DIPEA (0.708 g, 5.45 mmol) were added. The reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 A, 12 mL per min, gradient 1% to 8% MeOH in DCM]) to give ethyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate isomer 2 (0.147 g, 35.5%) as a white foam.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:15][O:16]3)=[CH:11][C:10]=2[C:26]#[N:27])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].Cl[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][N:32]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([NH:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:14][CH2:15][O:16]4)=[CH:11][C:10]=3[C:26]#[N:27])=[CH:28][CH:29]=2)=[O:3])=[N:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3)c(C#N)cc21
Reactant: Clc1ccc(Cl)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(Cl)cn4)cc3)c(C#N)cc21
Temperature: 80 °C
Yield: 13 %

Procedure:
tert-Butyl 7-(4-carbamoylphenoxy)-6-cyanochroman-4-carboxylate (30 mg, 0.076 mmol), 2,5-dichloropyridine (12 mg, 0.084 mmol), XPHOS (7.3 mg, 0.015 mmol), palladium (II) acetate (1.7 mg, 0.0076 mmol) and cesium carbonate (62 mg, 0.19 mmol) were diluted with dioxane (600 μL) in a 1 mL vial. The reaction was purged with argon for 3 minutes, capped and heated at 80° C. for 12 hours. The reaction was cooled and loaded directly onto a biotage 25 column and eluted with 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes to yield tert-butyl 7-(4-(5-chloropyridin-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (5 mg, 0.0099 mmol, 13% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:12]=3[C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:18][CH:17]=2)=[O:15])=[CH:5][CH:4]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:12]=3[C:13]=2[CH:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[CH:18][CH:17]=2)[OH:15])=[CH:7][CH:8]=1
Reactant: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)oc3cc(OC)ccc23)cc1
Solvent: CO
Product: CCN(CC)CCOc1ccc(C(O)c2c(-c3ccc(OC)cc3)oc3cc(OC)ccc23)cc1
Yield: 75 %

Procedure:
1.420 g (3 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzofuran-3-yl][4-[2-diethylaminoethoxy]phenyl]methanone was reduced to the carbinol by the method described in Example 1. This yielded 1.07 g of the title compound as an oil.