Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[C:5]2=[O:22].[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)[CH3:24]>C(#N)C>[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][N:29]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:22])[C:6]([C:19]([OH:21])=[O:20])=[CH:7][N:8]3[CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:3][C:2]=2[F:1])[CH2:28]1)[CH3:24]
Reactant: O=C(O)c1cn(CC(F)(F)F)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC(F)(F)F)c3c2F)C1
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To 0.76 g (2.33 mmol) of 6,7,8-trifluoro-1-(2,2,2-trifluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 7.0 ml of acetonitrile was added 0.355 g (2.33 mmol) of 1,8-diazobicyclo [5.4.0]undec-7-ene in 5 ml of acetonitrile followed by 0.29 g (2.33 mmol) of 3-[(ethylamino)methyl]-pyrrolidine. The mixture was refluxed for one hour and kept at room temperature overnight. The solids were collected and washed with ether to give 0.77 g of 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-1-(2,2,2-trifluoroethyl)-3-quinolinecarboxylic acid, mp 222°-224° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH:2]=1.[H-].[Na+].[CH2:19]([N:21]1[C:27](=[O:28])[C:26]([CH3:30])([CH3:29])[C:25](=[O:31])[N:24]([CH3:32])[C:23]2[CH:33]=[C:34]([O:37][CH2:38][CH2:39][CH2:40]I)[CH:35]=[CH:36][C:22]1=2)[CH3:20].C(O)C.[ClH:45]>CN(C=O)C.C(O)(C)C>[ClH:45].[CH2:19]([N:21]1[C:27](=[O:28])[C:26]([CH3:29])([CH3:30])[C:25](=[O:31])[N:24]([CH3:32])[C:23]2[CH:33]=[C:34]([O:37][CH2:38][CH2:39][CH2:40][N:9]3[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[C:8]3=[O:16])[CH:35]=[CH:36][C:22]1=2)[CH3:20]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Reactant: O=c1[nH]c2ccccc2n1-c1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)n(-c4cccnc4)c4ccccc43)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(Pyridin-3-yl)-1,3-dihydrobenzimidazole-2-one(0.2 g) was suspended in DMF(6 ml). Sodium hydride (55% in oil, 48 mg) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. 1-Ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.45 g) was added to the mixture. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to ice water(100 ml), followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure. A 0.5N-hydrogen chloride ethanol solution(1.9 ml) was added to an isopropyl alcohol solution of the residue. The mixture was condensed under reduced pressure. Ether was added to the residue. The generated insoluble matter was separated by filtration and dried to give the title compound(0.38 g) as a white powder.
Reaction SMILES: C1(C2CCC3C(=CC=C(OC4N=CC(N[S:25]([CH3:28])(=[O:27])=[O:26])=CC=4)C=3)O2)C=CC=CC=1.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[CH:37]1[CH2:46][CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:47][C:48]3[N:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=3)[CH:43]=2)[O:38]1>>[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[CH:37]1[CH2:46][CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:47][C:48]3[N:53]=[CH:52][C:51]([NH:54][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:50][CH:49]=3)[CH:43]=2)[O:38]1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2F)O3)nc1
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2F)O3)nc1

Procedure:
N-{6-[2-(2,4-difluorophenyl)chroman-6-yloxy]pyridin-3-yl}methane sulfonamide was prepared as described for N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]methane sulfonamide in Example 46 starting from 100 mg of 6-[2-(2,4-difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine (Example 70). The product was crystallised from a mixture of methanol and diethyl ether. 1H NMR (400 MHz, d6-DMSO) δ: 9.67 (s, 1H), 7.99 (d, 1H, J 2.8 Hz), 7.67 (dd, 1H, J 8.8, 2.8 Hz), 7.60 (m, 1H), 7.30 (m, 1H), 7.16 (m, 1H), 6.98 (d, 1H, J 8.8 Hz), 6.92-6.86 (m, 3H), 5.31 (dd, 1H, J 10.3, 2.3 Hz), 3.01 (m, 1H), 2.98 (s, 3H), 2.76 (m, 1H), 2.16 (m, 1H), 2.06 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][C:14]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:11])[CH3:10]>C(Cl)(Cl)Cl>[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:2]([CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH3:1])=[CH:15][C:14]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:11])[CH3:10]
Reactant: CNC1CCCCC1
Reactant: CC(=O)Nc1ccc(CBr)cc1C(C)(C)C
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(CN(C)C2CCCCC2)cc1C(C)(C)C

Procedure:
48 gm of N-methyl-cyclohexylamine were added to 56 gm of 4-acetylamino-3-tert.butyl-benzyl bromide in 500 ml of chloroform, and the mixture was refluxed for 1.5 hours. Subsequently, the reaction mixture was extracted three times with water, and the organic phase was evaporated. The residue was purified column-chromatographically on silicagel with chloroform/methanol (5:1), and 4-acetylamino-3-tert.butyl-N-cyclohexyl-N-methyl-benzylamine hydrochloride, m.p. 240°-243°C (decomp.), was crystallized from a solution of the purified base in absolute ethanol/ether by addition of absolute ethanolic hydrochloric acid.
Reaction SMILES: OOS([O-])=O.[K+].[C:7]1([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:15][N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]C.C[OH:42]>ClCCl>[C:7]1([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[O:42])[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CCCCCCCCCC
Reactant: c1ccc(-c2n[nH]c(-c3ccccc3)c2-c2ccccc2)cc1
Reactant: CO
Agent: O=S([O-])OO
Agent: [K+]
Solvent: ClCCl
Product: O=CCCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Temperature: -78 °C
Yield: 43.3 %

Procedure:
Oxone was bubbled through a solution of 3,4,5-triphenyl-lH-pyrazole-1-undecene (6.78 g, 15 mmol) in dichloromethane (175 mL) and methanol (0.73 g, 22 mmol) maintained at -78° C. for 1.5 hours. The ozone supply was removed, dimethylsulfide (30 mL) added and the mixture allowed to warm to room temperature over 2 hours. The solution was dried over sodium sulfate, concentrated in vacuo and the residue chromatographed on a column of silica gel. Elution with a mixture of hexane and ethyl acetate (9:1) gave 3,4,5-triphenyl-lH-pyrazole-1-decanal (2.93 g, 43%) as an oil. MS(CI): m/e =451 (MH+).
Reaction SMILES: C([Al:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][CH:7]([CH3:9])[CH3:8])C(C)C.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:16]=1[OH:23]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:16]=1[O:23][Al:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)C[Al](CC(C)C)Oc1c(Cl)cc(Cl)cc1Cl

Procedure:
In a manner analogous to that described in Example 1, 17.5 g of triisobutylaluminum and 17.4 g of 2,4,6-trichlorophenol are reacted in absolute toluene to give (2,4,6-trichlorophenoxy)diisobutylaluminum and this is then reacted with 22.4 g of pyridine-N-oxide-2-thiol to afford the title compound. The isolation of the product is carried out in analogous manner. The yield of (2,4,6-trichlorophenoxy)bis(2-pyridinethiolato)-aluminum N,N'-dioxide, a fine white powder with a melting point of 207°-208° C., is 28.6 g, about 68% of theory.
Reaction SMILES: Cl[CH:2]1[C:6](=O)[CH2:5][O:4][C:3]1=[O:8].[NH2:9][C:10]([NH2:12])=[S:11].[CH3:13][CH2:14][OH:15]>>[NH2:9][C:10]1[S:11][C:2]([C:3]([O:4][CH2:5][CH3:6])=[O:8])=[C:13]([CH2:14][OH:15])[N:12]=1
Reactant: NC(N)=S
Reactant: CCO
Reactant: O=C1COC(=O)C1Cl
Product: CCOC(=O)c1sc(N)nc1CO

Procedure:
A solution of 5.0 g (37 mmol) of 3-chlorofuran-2,4(3H,5H)-dione and 3.3 g (43 mmol) of thiourea in 50 ml EtOH was heated at reflux for 4 h. Solvent was removed and the residue was dissolved in water with 1N HCl added. The aqueous solution was basified with aqueous Na2CO3. Thick solids that formed were filtered, rinsed with water and dried in vacuo. NMR: 1.2 (t, 3H), 4.2 (q, 2H), 4.6 (s, 2H), 4.9 (br s, 1H), 7.8 (s, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1([C@@H:17]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOC(C)=O>[Cl-:1].[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N+:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([O:20][C:18](=[O:19])[C@@H:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22]2
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 56 %

Procedure:
A mixture of 2-chloroacetophenone (6.20 g, 40.3 mmol) and (R)-((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate) (Diastereoisomer 1 of C2) (12.3 g, 36.6 mmol) in EtOAc (100 ml) is stirred at RT for 2 days (UPLC-MS monitoring: complete conversion). The solvent is evaporated and the crude is purified by flash chromatography eluting with DCM/MeOH=95/5 to get 10.1 g of the title compound as a white solid (56% yield, chloride salt, single diastereoisomer).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[C:3]=1[Cl:9].C([Li])CCC.[CH3:15][S:16]SC.O>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:16][CH3:15])[C:3]=1[Cl:9]
Reactant: CSSC
Reactant: Clc1c(Br)cccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CSc1cccc(Br)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,3-dibromo-2-chlorobenzene (3.4 g, 12.6 mmol) in dry diethyl ether (60 ml), under nitrogen, at −78° C., was added dropwise n-butyllithium (2.5 M in hexane, 5.0 ml, 12.6 mmol). The mixture was stirred for 1 h after which dimethyldisulfide (1.0 ml, 13.9 mmol) was added dropwise. The resulting mixture was stirred at −78° C. for 30 min and then brought to ambient temperature. Water (100 ml) was added and the mixture was extracted with ethylacetate (3×100 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[O:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:41][N:42]([CH3:60])[C:43]1[S:44][CH:45]=[C:46]([C:48]2([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[N:47]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:27].[ClH:27].[CH2:1]([N:8]1[CH2:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15][N:51]2[CH2:50][CH2:49][C:48]([C:46]3[N:47]=[C:43]([N:42]([CH3:60])[CH3:41])[S:44][CH:45]=3)([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH2:53][CH2:52]2)[O:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1nc(C2(c3ccccc3)CCNCC2)cs1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CN(Cc2ccccc2)C(=O)CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)c1nc(C2(c3ccccc3)CCN(CCC3(c4ccc(Cl)c(Cl)c4)CN(Cc4ccccc4)C(=O)CO3)CC2)cs1
Product: Cl
Yield: 131.5 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 41 from 1.1 g of the compound obtained in step B of EXAMPLE 14, 1.3 g of 4-[2-(dimethylamino)thiazol-4-yl]-4-phenylpiperidine p-toluenesulfonate, 0.97 g of K2CO3 and 4 ml of DMF to give 0.76 g of the expected product. M.p.=155°-160° C.
Reaction SMILES: [CH:1]1[C:5]2=[C:6]3[C:10]([CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:8]=[CH:7]3.N1CCCCC1>CN(C=O)C>[CH2:7]1[C:6]2=[C:5]3[C:4](=[CH:12][CH:11]=[C:10]2[NH:9][CH2:8]1)[NH:3][C:2]([C:13]([O:15][CH3:16])=[O:14])=[CH:1]3
Reactant: COC(=O)C1=Cc2c3c(ccc2=N1)=NC=C3
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)c1cc2c3c(ccc2[nH]1)NCC3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 374.6 %

Procedure:
A solution of 3 (22 mg, 0.02 mmol) in DMF (2 mL) was treated with 5% piperidine in DMF (2 mL). The reaction mixture was stirred for 5 min at 25° C. The final product was purified by Prep HPLC (SymmetrPrep C18, 7 μm, 19×150 mm column), eluted at 10 ml/min (0.01% TFA in water/acetonitrile) with a gradient: 10% acetonitrile in 5 min, 10% to 50% acetonitrile in 15 min, maintaining 50% acetonitrile in 5 min, 50% to 100% acetonitrile in 5 min, to obtain 4 (16.2 mg, 93%). MS: calcd for C41H44BrN9O6 (M+H) m/z 838.26 found 839.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([I:19])=[C:11]([N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23]C=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:52][C:53]([O:55][CH3:56])=[O:54])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:57]1COCC1>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([I:19])=[C:11]([N:20]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:21][CH2:22][CH2:23]/[CH:57]=[CH:52]/[C:53]([O:55][CH3:56])=[O:54])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCCC=O)c1cc(OCc2ccccc2)c2ccccc2c1I
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Product: COC(=O)/C=C/CCCN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)c2ccccc2c1I
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
A solution of 110 (13.3 mg, 24.4 μmol) in THF (0.3 mL) was treated with methyl (triphenylphosphoranylidene)acetate (23.9 mg, 71.5 μmol, 3 equiv). The reaction mixture was stirred for 48 h at 25° C. and the solvent removed under vacuum. Chromatography (SiO2, 10-25% EtOAc-hexane gradient elution) afforded 112 (9 mg, 14 mg theoretical, 63%) as an oil: 1H NMR (CDCl3, 400 MHz) δ 8.32 (d, J=8.2 Hz, 1H), 8.20 (d, J=8.2 Hz, 1H), 7.61-7.48 (m, 5H), 7.42-7.32 (m, 2H), 6.91 (m, 1H), 6.74 and 6.64 (two s, 1H), 5.79 (d, J=15.5 Hz, 1H), 5.31-5.23 (m, 2H), 3.81 (ddd, J=14.0, 9.6, 3.6 Hz, 1H), 3.70 (s, 3H), 3.35 (m, 1H), 2.18 (m, 2H), 1.75-1.55 (m, 2H), 1.29 and 1.24 (two s, 9H); IR (film) νmax 2975, 2947, 1702, 1658, 1471, 1391, 1366, 1307, 1272, 1162 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][C:17]([CH3:20])([CH3:19])[C:16]3[C:11](=[CH:12][N:13]=C(C#N)[CH:15]=3)[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-:23].[Na+].Cl.[CH2:26]([OH:28])[CH3:27]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][C:17]([CH3:20])([CH3:19])[C:16]3[C:11](=[CH:12][N:13]=[C:27]([C:26]([OH:23])=[O:28])[CH:15]=3)[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [OH-]
Reactant: CCO
Reactant: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2cnc(C#N)cc21
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2cnc(C(=O)O)cc21
Temperature: 90 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a stirred mixture solution of 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carbonitrile (315.0 mg, 1.0 mmol) in ethanol (10.0 mL) was added 50% sodium hydroxide in water (3.5 mL). The reaction mixture was stirred at 90° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid (317.9 mg, 95%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=335.1.
Reaction SMILES: CC1(NC2N=CC(C(F)(F)F)=CN=2)CCCC1NC(C1C(C2N=CC=CN=2)=CC=CN=1)=O.[CH3:33][C:34]1([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][N:42]=2)[CH2:38][CH2:37][CH2:36][CH:35]1[NH2:39].[N:51]1[N:52]([C:56]2[C:57]([C:62](O)=[O:63])=[N:58][CH:59]=[CH:60][CH:61]=2)[N:53]=[CH:54][CH:55]=1.C(N(CC)CC)C>>[CH3:33][C:34]1([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:48])[F:49])=[CH:43][N:42]=2)[CH2:38][CH2:37][CH2:36][CH:35]1[NH:39][C:62]([C:57]1[C:56]([N:52]2[N:53]=[CH:54][CH:55]=[N:51]2)=[CH:61][CH:60]=[CH:59][N:58]=1)=[O:63]
Reactant: CC1(Nc2ccc(C(F)(F)F)cn2)CCCC1N
Reactant: O=C(O)c1ncccc1-n1nccn1
Agent: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-c1ncccn1
Solvent: CCN(CC)CC
Product: CC1(Nc2ccc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-(2-methyl-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl)-3-(pyrimidin-2-yl)pyridine-2-carboxamide (Example 153) from 1-methyl-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine (Intermediate 51; 85 mg, 0.33 mmol), 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 75 mg, 0.33 mmol) and triethylamine (0.14 ml, 0.98 mmol) except this was then recrystallised from diisopropyl ether/pentane and then triturated with diethyl ether to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[F:17]C1C=C2C(=CC=1)N=CC(C(OCC)=O)=C2O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:17])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1O
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Product: CCOC(=O)c1cnc2ccc(F)cc2c1Cl

Procedure:
The title compound was prepared following the procedure described in Step 2 for the synthesis of 3a using 2b instead of 2a. 1H NMR (CDCl3) δ (ppm): 1.47 (3H, t, J=7.08 Hz), 4.51 (2H, q, J=7.08 Hz), 7.63 (1H, m), 8.02 (1H, dd, J=9.52, 2.68 Hz), 8.15 (1H, dd, J=9.27, 5.37 Hz), 9.15 (1H, s). m/z 254.6 (MH+).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][I:21]>>[I-:21].[CH3:20][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CI
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [I-]
Yield: 95.5 %

Procedure:
Starting with 10.0 g (38.1 mmol) of triphenylphosphine and 6.8 g (48 mmol, 1.3 eq) of methyl iodide, 14.7 g (36.4 mmol, 95.4%) of methyltriphenylphosphonium iodide was obtained: mp 185.9°-186.8° C.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[CH3:19][N:20]1[CH2:24][CH2:23][C@@:22]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH2:25][C:26]#[CH:27])[C:21]1=[O:36].N(CC)CC>C1COCC1.[Cu](I)I>[CH3:19][N:20]1[CH2:24][CH2:23][C@@:22]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])([CH2:25][C:26]#[C:27][C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[C:21]1=[O:36]
Reactant: C#CC[C@]1(NC(=O)OC(C)(C)C)CCN(C)C1=O
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCNCC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Temperature: 20 °C
Reaction time: 18 h
Yield: 106.7 %

Procedure:
Copper Iodide (149.46 mg, 0.7800 mmol), followed by PdCl2(Ph3P)2 (275.41 mg, 0.3900 mmol) was added portionwise to a solution of 2-iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (4 g, 10.99 mmol) (which may be prepared as described in Description 12), tert-butyl N-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (1.98 g, 7.85 mmol) (which may be prepared as described in Description 4) and Et2NH (4.06 mL, 39.24 mmol) in THF (50 mL) under N2 and the reaction was stirred at 20° C. for 18 hrs. The solvent was evaporated and the residue was suspended in EtOAc and washed with water/sat. aq. NaHCO3. The organics were collected, dried (Na2SO4) and the solvent evaporated to afford a brown oil. This was purified using a Biotage SP4, with a 100 g SNAP cartridge, eluting with 50 to 100% EtOAc/i-hexane to afford tert-butyl N-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (D13a) (4.09 g, 8.3726 mmol) as a pale yellow foam. The NMR was the same as that for the R isomer produced in Description 13 but also contained traces of ethyl acetate and impurities.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[NH3:15]>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH2:15])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: N
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
6-bromo-2-naphthoic acid (2 g, 7.97 mmol) was stirred in thionyl chloride (13.28 ml) at 70° C. for 16 h. Solvent was evaporated, and the residue was dissolved in CH2Cl2 and concentrated again. To the acid chloride intermediate was added ammonia (7N in MeOH, 13.66 ml, 96 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, diluted in ethyl acetate and filtered. The solid was rinsed with ethyl acetate and then dried. The title compound 2a (1.802 g, 90%) was isolated as beige solid. LC-MS (M+1) 251.9, t=1.34 min.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1.[CH2:19]([C:21]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24])[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.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>[CH2:19]([C:21]1[C:22]([CH:23]=[O:24])=[CH:25][CH:26]=[CH:27][C:28]=1[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1)[CH3:20]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Cc1ccc(-c2nc(Br)ns2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1c(C=O)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Temperature: 120 °C
Yield: 89.2 %

Procedure:
To a solution of 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-(2-methylpropyl)benzonitrile (D60) (500 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (424 mg) and tripotassium phosphate (988 mg) in N,N-dimethylformamide (DMF) (4 mL) and water (1 mL) stirred under nitrogen was added Pd(Ph3P)4 (179 mg). The mixture was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulphate, concentrated and purified by column chromatography to give 5-[3-(2-ethyl-3-formylphenyl)-1,2,4-thiadiazol-5-yl]-2-(2-methylpropyl)benzonitrile (D63) (520 mg). δH (CDCl3, 400 MHz): 1.00 (6H, d), 1.37 (3H, t), 2.81 (2H, d), 3.38 (2H, q), 4.11 (1H, m), 7.48 (2H, m), 8.02 (1H, d), 8.14 (2H, m), 8.30 (1H, d), 10.48 (1H, s). MS (ES): C22H21N3OS requires 375. found 376.1 (M+H+).