Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1O[C:8](=[S:16])OC1C=CC=CN=1.[CH2:17]([N:20]([CH2:32][CH2:33][CH3:34])[CH:21]1[CH2:30][C:29]2[C:24](=[C:25]([NH2:31])[CH:26]=[CH:27][CH:28]=2)[NH:23][CH2:22]1)[CH2:18][CH3:19]>C1COCC1>[CH2:32]([N:20]([CH2:17][CH2:18][CH3:19])[CH:21]1[CH2:30][C:29]2[C:24]3=[C:25]([NH:31][C:8](=[S:16])[N:23]3[CH2:22]1)[CH:26]=[CH:27][CH:28]=2)[CH2:33][CH3:34]
Reactant: CCCN(CCC)C1CNc2c(N)cccc2C1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: C1CCOC1
Product: CCCN(CCC)C1Cc2cccc3[nH]c(=S)n(c23)C1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
Di (2-pyridyl)thiocarbonate (1.6 g, 7.2 mmol) was added to a stirred solution of 1,2,3,4-tetrahydro-N3,N3 -dipropyl-3,8-quinolinediamine (1.6 g, 6.7 mmol) in THF (50 mL). The solution was stirred for 1 hour, evaporated, and partitioned between chloroform and water. The chloroform phase was evaporated and chromatographed on silica gel using ethyl acetate:hexane (1:9) as the initial eluant to give 1.6 g of product. Crystallization from cyclohexane gave 1.3 g (67% of 5-(dipropylamino)-5,6-hydro-4H-imidazo(4,5,1-ij)quinolin-2(1H)-thione, mp 150°-151° C. Anal. Calcd. for C16H23N3S: C, 66.39; H, 8.01; N, 14.52; S, 11.08. Found: C, 66.50; H, 8.18; N, 14.56; S, 11.02.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>ClCCCl>[Cl:18][CH2:14][CH:11]1[CH2:12][CH2:13][N:9]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH2:10]1
Reactant: CC(c1ccccc1)N1CCC(CO)C1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: CC(c1ccccc1)N1CCC(CCl)C1
Yield: 100 %

Procedure:
A solution of 0.50 g (2.44 mmol) [3R-(R*,R*)]-1-(1-phenylethyl)-3-pyrrolidinemethanol in 5 ml 1,2-dichloroethane was treated with 2 ml thionyl chloride, refluxed two hours, evaporated, and crystallized by trituration with ether to afford 0.64 g (100%) of the title compound as the hydrochloride mp 140°-146 ° C., [α]D +27.8° C. (c, 1.07, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[C:17]=1[F:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:13][CH3:14])([CH2:15][CH3:16])[C:6]=3[C:17]=2[F:18])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)c(F)c21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(Cl)c3)c(F)c21

Procedure:
Prepared from 6-amino-4,4-diethyl-5-fluoro-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-chloro-4-fluorophenylboronic acid according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 8.03 (s, 1H), 7.32 (t, J=8.8 Hz, 1H), 7.26 (t, J=9.1 Hz, 1H), 6.92 (m, 2H), 6.83 (m, 1H), 3.29 (s, 3H), 2.12 (m, 2H), 1.92 (m, 2H), 0.84 (t, J=7.2 Hz, 6H); MS (ESI) m/z 381/383 ([M+H]+); MS (ESI) m/z 379/381 ([M−H]−); Anal. calcd for C19H19ClF2N2O2: C, 59.93; H, 5.03; N, 7.36. Found: C, 59.68; H, 4.92; N, 7.14.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[F:21][C:22]([F:31])([F:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:29][C:26]3[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:30])[F:31])=[CH:24][CH:25]=3)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: CCCCN1CCN(C(=O)c2ccc(CNc3ccc(C(F)(F)F)cc3)cc2)CC1

Procedure:
Prepared from the product of Example 13 and 4-trifluoromethyl-phenylamine.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)#[N:2].O.N.[ClH:14]>[Ni].CO>[ClH:14].[NH2:2][CH2:1][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1
Reactant: N#C[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
In order to carry out the reaction advantageously on an industrial scale, trans-4-cyanocyclohexane-1-carboxylic acid is hydrogenated at a room temperature under pressure in a hydrous methanol made alkaline by the addition of ammonia water in the presence of Raney nickel, and then the catalyst is filtered and the solvent is removed by distillation. When lower alkyl trans-4-cyanocyclohexane-1-carboxylate is used as a starting material, it is subjected to the same reaction and treatment as above, and the residue is hydrolyzed with dilute hydrochloric acid in a hot water bath to produce trans-4-aminomethyl-cyclohexane-1-carboxylic acid hydrochloride. The reaction solution is passed through a column of a weakly basic ion-exchange resin to obtain trans-4-aminomethylcyclohexane-1-carboxylic acid in an yield of from 85 to 95 percent.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[O:22])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2]>Cl.O1CCOCC1>[CH:36]1([CH2:35][C@H:24]([NH:23][C:21]([N:17]2[CH2:18][CH2:19][CH2:20][C@@H:15]([C@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:7][CH2:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:16]2)=[O:22])[CH2:25][NH:26][CH3:27])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CCOCCCC[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CCOCCCC[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CNC)CC2CCCCC2)C1
Yield: 98.2 %

Procedure:
tert-butyl (S)-2-((S)-3-((R)-5-ethoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate (40.7 mg, 0.071 mmol) was stirred in HCl/dioxane (4 N, 4 mL) at rt until no starting material remained. The solvent was removed to give (3S)—N—((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-5-ethoxy-1-phenylpentyl)-piperidine-1-carboxamide (32.9 mg, 91%) as its HCl salt. 1H NMR (CD3OD) δ 0.9 (m, 3H), 1.0 (m, 2H), 1.11 (t, 3H), 1.2-2.0 (20H), 2.40 (m, 1H), 2.65 (m, 1H), 2.70 (s, 3H), 3.93 (m, 1H), 3.05 (m, 2H), 3.31 (m, 1H), 3.40 (q, 2H), 3.91 (d, 1H), 4.13 (m, 2H), 7.13 (2H), 7.19 (1H), 7.28 (2H). MS ESI+ve m/z 472 (M+1).
Reaction SMILES: [NH2:1]/[C:2](=[N:27]\[OH:28])/[C:3]([NH:9][C:10]([C:12]1[CH:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:15]([CH:24]2[CH2:26][CH2:25]2)=[CH:14][N:13]=1)=[O:11])([CH2:5][CH:6]1[CH2:8][CH2:7]1)[CH3:4].[N:29]1(C#N)CCCC[CH2:30]1>C(OCC)(=O)C>[NH2:29][C:30]1[O:28][N:27]=[C:2]([C:3]([NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])[C:15]([CH:24]3[CH2:25][CH2:26]3)=[CH:14][N:13]=2)=[O:11])([CH3:4])[CH2:5][CH:6]2[CH2:8][CH2:7]2)[N:1]=1
Reactant: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)/C(N)=N/O
Reactant: N#CN1CCCCC1
Solvent: CCOC(C)=O
Product: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1noc(N)n1
Temperature: 130 °C
Yield: 65.9 %

Procedure:
A mixture of N-[(2Z)-2-amino-1-(cyclopropylmethyl)-2-hydroxyimino-1-methyl-ethyl]-5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 165a, 30 mg, 74.9 μmol) in piperidine-1-carbonitrile (130 mg, 130 μl, 1.18 mmol) was heated at 130° C. in a sealed tube for 2 hours. The reaction mixture was cooled to room temperature and was diluted with ethyl acetate. The organic phase was washed with water. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (21 mg, 67%). MS (ESI, m/z): 426.6 (M+H+).
Reaction SMILES: C([O:5][C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)C(O)=O)(C)(C)C.[C:29]([O:33][C@@H:34]([C:37]1[C:38]([C:52]2[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([C:48]([F:51])([F:50])[F:49])[CH:41]=[CH:40]2)[CH2:35][OH:36])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C@@H:34]([C:37]1[C:38]([C:52]2[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=2)=[C:39]2[C:44](=[CH:45][C:46]=1[CH3:47])[N:43]=[C:42]([C:48]([F:50])([F:49])[F:51])[CH:41]=[CH:40]2)[C:35]([OH:5])=[O:36])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(Cl)cc2n1
Reactant: Cc1cc2nc(C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2nc(C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quinolin-6-yl)acetic acid (7J) was prepared following the procedure used to prepare compound 1L of Example 1 except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quinolin-6-yl)ethanol (7I) was used instead of compound 1K. 1H-NMR 300 MHz, (CD3OD) δ 8.01 (s, 1H), 7.95 (d, 1H), 7.71 (d, 1H), 7.65-7.55 (m, 2H), 7.35 (d, 1H), 5.24 (s, 1H), 2.71 (s, 3H), 0.99 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C23H22ClF3NO3: 452.9. Found: 452.1, 454.1.
Reaction SMILES: N[C:2]1[C:3]2[C:27]3(CCOC3)[C:26](=[O:32])[NH:25][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)[N:7]=1.[Se](=O)=[O:34]>O1CCOCC1>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:6]2[N:7]=[CH:2][C:3]3[C:27](=[O:34])[C:26](=[O:32])[NH:25][C:4]=3[N:5]=2)=[N:9]1
Reactant: O=[Se]=O
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1C1(CCOC1)C(=O)N2
Solvent: C1COCCO1
Product: O=C1Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2C1=O

Procedure:
2.00 g (5.550 mmol) of Example 4 were initially charged in dioxane (200 ml), 3.079 g (27.751 mmol) of selenium dioxide were added and the mixture was heated at reflux for 2 h. After cooling, the mixture was filtered and the filtrate was concentrated and purified by chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 1:1). This gave 890 mg of the title compound (42% of theory).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:30][CH3:31])=[C:21]([NH:23][C:24](=[O:29])[C:25](F)(F)F)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].C1COCC1.[CH:39]1[CH:43]=[C:42](CC(Cl)=O)[S:41][CH:40]=1>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:30][CH3:31])=[C:21]([NH:23][C:24](=[O:29])[CH2:25][C:40]4[S:41][CH:42]=[CH:43][CH:39]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Reactant: O=C(Cl)Cc1cccs1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A solution of N-[5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (250 mg, 0.56 mmol) and 1M LiOH (1.30 mL, 1.39 mmol) in 10:1 THF:H2O (5 mL) was heated at 50° C. overnight. After removal of THF by rotary evaporation, the reaction mixture was redissolved in EtOAc and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4. Following filtration, the solvent was removed by rotary evaporation. After high vacuum removal of the residual solvent, the crude mixture was dissolved in THF (5 mL) and to this was added thiophene-2-acetylchloride (0.10 mL, 0.84 mmol). After overnight stirring, water (0.5 mL) was added and THF removed by rotary evaporation. The reaction mixture was redissolved in DCM (25 mL) washed with saturated NaHCO3 (10 mL), water (10 mL) and brine (10 mL). Organics were dried over MgSO4, filtered and filtrate concentrated under reduced pressure to afford the desired amide (210 mg, 79%) as an off-white solid. ES-LC/MS m/z=476 [M+H]−.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].Br[C:15]1[N:16]=[C:17]([O:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[S:18][CH:19]=1>>[C:31]([O:30][C:28]([N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][O:20][C:17]2[S:18][CH:19]=[C:15]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)[N:16]=2)[CH2:27][CH2:26]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2nc(Br)cs2)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2nc(-n3ccc4cc(S(C)(=O)=O)ccc43)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using 5-(methylsulfonyl)-1H-indole (intermediate-21) and tert-Butyl 4-(((4-bromothiazol-2-yl)oxy)methyl)piperidine-1-carboxylate (intermediate 47) (0.013 g, 10%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:7][N:6]=[N:5][CH:4]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:25]=1)[C:20]([OH:22])=O>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:7][N:6]=[N:5][CH:4]=1)=[O:22]
Reactant: CNc1cnncc1-c1ccccc1C
Reactant: CS(=O)(=O)c1cc(Cl)cc(C(=O)O)c1
Product: Cc1ccccc1-c1cnncc1N(C)C(=O)c1cc(Cl)cc(S(C)(=O)=O)c1
Yield: 44 %

Procedure:
The title compound was prepared in analogy to example 1, from methyl-(5-o-tolyl-pyridazin-4-yl)-amine and 3-chloro-5-methanesulfonyl-benzoic acid. A second purification step using preparative HPLC (Gemini NX column) with a gradient of acetonitrile:water with 0.05% formic acid (80:20 to 98:2) gave the desired compound as a colorless solid (44%). MS (ESI+): m/z=416.083 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]([O:26]CC)=[CH2:25])CCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:24](=[O:26])[CH3:25])=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cn2)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CC2)nc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
To a solution of [1-(5-Iodo-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (100 mg, 0.278 mmol) in anhydrous DMF (1 mL) was added tributyl-(1-ethoxy-vinyl)-stannane (0.103 mL, 0.305 mmol) followed by tetrakis(triphenylphosphane)palladium (0) (32.1 mg, 0.028 mmol). The mixture was stirred at 100° C. under an atmosphere of argon. After 16 h, pyridinium p-toluenesulfonate (77.0 mg, 0.306 mmol) was added along with 0.5 mL of water and the mixture was stirred at rt for 1 h. The reaction was diluted with 10 mL of 10% citric acid and was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (10 g biotage SNAP column, 5-40% EtOAc in hexanes) to give the title compound as a yellow solid (74.7 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[N:4][N:5]([CH2:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].[BH4-].[Na+].CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:24]([F:27])([F:25])[F:26])=[N:4][N:5]([CH2:8][CH:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[OH:10])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(O)C1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103.7 %

Procedure:
A solution of tert-butyl 4-(2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)piperidine-1-carboxylate (1.0 g, 2.440 mmol) in anhydrous CH2Cl2 (20 mL) was treated with sodium borohydride (0.055 g, 1.464 mmol), followed by anhydrous MeOH (4 mL). The mixture was stirred at RT for 1.5 h and then concentrated on a rotary evaporator. The resultant residue was treated with 4 M HCl in dioxane (10 mL). After stirring for 2 h, the mixture was concentrated and this residue was made basic with a minimum amount of saturated NaHCO3. The mixture was lyophilized. The resultant lyopholate was treated with CH2Cl2 (50 mL), stirred vigorously for 5 minutes, and then filtered (CH2Cl2 washes). The combined CH2Cl2 filtrates were concentrated to give 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(piperidin-4-yl)ethanol (0.79 g, 2.53 mmol, 104% yield) as an off-white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 4.09-4.17 (1 H, m), 3.95-4.02 (1 H, m), 3.86 (1 H, ddd, J=8.84, 6.21, 2.31 Hz), 3.11-3.19 (2 H, m), 2.62 (2 H, tt, J=12.28, 3.10 Hz), 2.29 (3 H, s), 1.84 (1 H, d, J=12.96 Hz), 1.64-1.71 (1 H, m), 1.55-1.64 (1 H, m), 1.34-1.44 (2 H, m).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:13][N:12]([CH3:14])[CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCCN1CCNCC1
Yield: 43.6 %

Procedure:
A mixture of 100 g (1.2 mole) of piperazine, 72 g (0.455 mole) of 3-chloro-N,N-dimethylpropanamine, hydrochloride and 110 g (1.3 mole) of sodium bicarbonate in 500 ml of ethanol was heated under reflux for 7 hr, allowed to cool, filtered and concentrated to dryness under vacuum. The concentrate was slurried in dichloromethane and filtered. The filterate was concentrated and then distilled under water pump pressure (~5 mm) to afford 34 g (44%) of the desired product, bp 100°-102°/5 mm.
Reaction SMILES: CC([O-])(C)C.[K+].C[CH2:8][O:9][C:10]([CH2:12]P(OCC)(OCC)=O)=[O:11].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23](=O)[CH2:22]1>CN(C=O)C.O=O>[CH3:8][O:9][C:10](=[O:11])[CH2:12][C:23]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:21][CH:22]=1
Reactant: O=C1COc2ccccc21
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1coc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
KOtBu (0.673 g, 6 mmol) was dissolved in dry DMF (10 ml) with exclusion of oxygen. Phosphonoacetic acid triethyl ester (0.87 ml, 6 mmol) was then added to the mixture. After 20 min a solution of benzofuran-3(2H)-one (0.536 g, 4 mmol) in dry DMF (10 ml, argon atmosphere) was added to this mixture. The reaction mixture was stirred at room temperature for 1 h and thereafter poured on to ice (50 ml) for working up. The mixture obtained was extracted with diethyl ether (4×20 ml). The organic phase was washed with water (4×20 ml), dried with Na2SO4 and then concentrated. The product formed was purified by column chromatography [silica gel 60 (50 g); cyclohexane, ethyl acetate (4:1)] and obtained in a yield of 0.372 g (48%) as a yellowish oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[C:15](=[O:20])N(OC)C)=[O:7])([CH3:4])[CH3:3].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[CH:22]1>>[C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[C:15]([C:22]1[O:21][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=1)=[O:20])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: c1ccc2occc2c1
Reactant: CON(C)C(=O)C1CN(C)CCN1C(=O)OC(C)(C)C
Product: CN1CCN(C(=O)OC(C)(C)C)C(C(=O)c2cc3ccccc3o2)C1
Yield: 52 %

Procedure:
The title compound (1.81 g, 52%) was prepared from (RS)-2-(methoxy-methyl-carbamoyl)4-methyl-piperazine-1-carboxylic acid dimethyl-ethyl ester, D54 (2.9 g, 10.1 mmol) and benzofuran (0.74 g, 10.1 mmol) using the method of Description 2.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[S:5]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O)([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6].O>CN(C=O)C>[C:11]1([CH3:12])[CH:10]=[CH:9][C:8]([S:5]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])(=[O:6])=[O:7])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOCCN=[N+]=[N-])cc1
Temperature: 110 °C
Yield: 16.5 %

Procedure:
Sodium azide (0.47 g, 7.24 mmol) added to a solution of diethyleneglycol ditosylate (3 g, 7.24 mmol) in DMF (30 mL) and the resulting mixture was heated to 110° C. for 5 hours. The reaction mixture was poured into chilled water (125 mL) and the product was extracted with ethyl acetate (3×100 mL), the collected organic extracts were washed with water (3×100 mL), brine and dried over MgSO4. The crude product was purified on SiO2 and DCM/MeOH 0-100% gradient as eluant to yield 0.34 g (16%) of 7 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.45 (s, 3H), 3.16 (t, J=4.8 Hz, 2H), 3.60 (t, J=4.8 Hz, 2H), 3.70 (t, J=4.8 Hz, 2H), 4.17 (t, J=4.8 Hz, 2H), 7.35 (d, J=8 Hz, 2H), 7.81 (d, J=8 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 21.6, 50.6, 68.7, 69.1, 70.2, 128.0, 129.9, 133.0, 144.9; MS ESI (m/z): [M+H]+ calcd. for C11H15N3O4S, 286.08. found 286.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[CH:23]1([CH2:26][C:27](O)=[O:28])[CH2:25][CH2:24]1>>[CH:23]1([CH2:26][C:27]([NH:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([NH:11][CH:7]2[C:8]4[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[CH2:5][CH2:6]2)[CH:21]=[CH:20]3)=[O:28])[CH2:25][CH2:24]1
Reactant: O=C(O)CC1CC1
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Product: O=C(CC1CC1)Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and cyclopropyl acetic acid; MS: m/e=376.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].[CH2:11]([N:13]([CH2:24][CH3:25])[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)=[O:15])[CH3:12].[Cl-].[NH4+]>O1CCCC1>[CH2:24]([N:13]([CH2:11][CH3:12])[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]([OH:21])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])=[CH:18][CH:17]=1)=[O:15])[CH3:25]
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Reactant: COc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(O)c2ccccc2OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 2-bromoanisole (12.1 ml) dissolved in tetrahydrofuran (200 ml) was added with magnesium (2.368 g) and stirred at 60° C. for 1 hour to prepare a Grignard reagent. This Grignard reagent was added with a solution of 4-diethylcarbamoylbenzaldehyde (10.0 g) dissolved in tetrahydrofuran (200 ml) with ice cooling and stirred at room temperature for 1 hour. The reaction mixture was added with saturated aqueous ammonium chloride (400 ml) with ice cooling to quench the reaction and then extracted twice with dichloromethane (400 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:1) to obtain 14.14 g of the title compound. Yield: 93%.