Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4](Cl)[N:3]=1.NC(N)=[S:22].C(=O)(O)[O-].[Na+]>O>[NH2:1][C:2]1[NH:3][C:4](=[S:22])[C:5]2[N:6]=[CH:7][N:8]([C@H:11]3[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]3)[C:9]=2[N:10]=1
Reactant: NC(N)=S
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2C[C@H](CO)[C@@H](O)C2)c(=S)[nH]1
Yield: 71.1 %

Procedure:
(+)-(1S,2R,4R)-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)cyclopentanol, (1.70 g, 6.00 mmol) and thiourea (456 mg, 6.00 mmol) were refluxed in water (15 mL) for 1.0 hour. The cooled solution was adjusted to pH5 with saturated aqueous sodium bicarbonate. The resulting precipitate was filtered, washed with water and dried to give title compound as white powder (1.20 g, 71%); m.p. 290-291° dec; mass spectrum (Cl, CH4) 282 (M+1); 1H-NMR (DMSO-d6)δ: 11.90 (br s, 1, NH), 8.03 (s, 1, H-8), 6.78 (br s, 2, NH2), 4.95-4.70 (m, overlapping d at 4.78, J=27 Hz, total 2, CHN and OH), 4.7-4.6 (m, 1, CH2OH), 4.1-4.0 (m, 1, CHOH), 3.6-3.4 (m, 2, CH2O), 2.4-2.2 (m, 1, CH), 2.2-1.9 (m, 3, methylene), 1.7-1.5 (m, 1, 1/2CH2); [α]20589 +6.43°, [α]20578 +6.71°, [α]20546 +7.43°, [α]20436 +8.43°, [α]20 365 +8.43° (c=0.70, 0.1N NaOH).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22](O)=[O:23])[C:17]=1[CH3:25].C(Cl)(=O)C(Cl)=O.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]2)=[O:23])[C:17]=1[CH3:25]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: Cc1c(C(=O)O)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCC(N3CCOCC3)CC2)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 0.080 g (0.24 mmol) of 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid (Example 16C]) in 1.5 ml of CH2Cl2 was treated at RT with 1 drops of DMF. 0.02 ml (0.29 mmol, 1.2 eq) of oxalyl chloride in 0.5 ml CH2Cl2 were added dropwise and stirring was continued for 1 h. The solution was evaporated, redissolved in 1 ml of CH2Cl2, cooled (0° C.) and treated with a solution of 0.041 g (0.24 mmol, 1 eq) of 4-(piperidine-4-yl)-morpholine and 0.07 ml (0.48 mmol, 2 eq) of triethylamine in 0.5 ml of CH2Cl2. The reaction was stirred for 3 h at this temperature, then partitioned three times between EtOAc and aqueous saturated NaHCO3, dried over Na2SO4 and evaporated to give 0.134 g (quant.) of the title compound as light yellow foam. MS: 485.3 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:25]=[CH:24][C:6]2[C:7]([C:10]3[CH:15]=[C:14]([CH2:16][CH2:17][CH3:18])[C:13]([O:19]C)=[CH:12][C:11]=3[CH2:21][CH2:22][CH3:23])=[N:8][O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>ClCCCl>[OH:19][C:13]1[C:14]([CH2:16][CH2:17][CH3:18])=[CH:15][C:10]([C:7]2[C:6]3[CH:24]=[CH:25][C:3]([OH:2])=[CH:4][C:5]=3[O:9][N:8]=2)=[C:11]([CH2:21][CH2:22][CH3:23])[CH:12]=1
Reactant: CCCc1cc(-c2noc3cc(OC)ccc23)c(CCC)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCCl
Product: CCCc1cc(-c2noc3cc(O)ccc23)c(CCC)cc1O
Temperature: 60 °C
Reaction time: 15 h
Yield: 91.8 %

Procedure:
To a solution of 6-methoxy-3-(4-methoxy-2,5-dipropylphenyl)-1,2-benzisoxazole (193 mg, 0.57 mmol) in 1,2-dichloroethane (6.0 mL) at 0° C. was added BBr3 (5.7 mL, 5.7 mmol, 1.0 M in CH2Cl2) slowly. The resulting brown solution was stirred at 60° C. for 15 hr, cooled to 0° C., quenched carefully with water, and extracted in EtOAc (2×30 mL) with 2 N HCl (2×20 mL). Purification (twice) by flash chromatography with silica gel (gradient to 40% EtOAc/hexanes) furnished the title compound as a light yellow solid (163 mg, 93% yield): mp 162-163° C.; 1H NMR (300 MHz, acetone-d6) δ 0.80 (t, 3H, J=7.3 Hz), 0.97 (t, 3H, J=7.4 Hz), 1.52 (m, 2H), 1.67 (m, 2H), 2.65 (two overlapping triplets, 4H), 6.91 (s, 1H), 6.95 (dd, 1H, J=8.6, 2.0 Hz), 7.04 (d, 1H, J=1.8 Hz), 7.26 (s, 1H), 7.46 (d, 1H, J=8.6 Hz), 8.89 (broad s, 2H); MS m/e 312 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[C:19](Cl)(=[O:21])[CH3:20].O>N1C=CC=CC=1>[C:19]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1)(=[O:21])[CH3:20]
Reactant: COC(=O)c1nc(N)sc1-c1ccc(SC)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1nc(NC(C)=O)sc1-c1ccc(SC)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Methyl 2-amino-5-[4-(methylthio)phenyl]-1,3-thiazole-4-carboxylate (8.8 g) was dissolved in pyridine (88 ml), and then acetyl chloride (6.7 ml) was added dropwise to the solution at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes and at 50° C. for 2 hours. After cooled to 0° C., water was added to the solution. The precipitate was filtered in vacuo, and the solid was washed with ethyl ether to give methyl 2-(acetylamino)-5-[4-(methylthio)phenyl]-1,3-thiazole-4-carboxylate (9.3 g) as an off-white solid.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O.CN(C)C=O>[F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:37]([CH:34]4[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32][CH2:33]4)=[O:38])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6]
Reactant: Nc1cc(Oc2ccc3c(ccn3C(=O)NCCF)c2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(ccn4C(=O)NCCF)c3)ccn2)CC1

Procedure:
N1-(2-Fluoroethyl)-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide (500 mg), 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid (440 mg), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop Reagent) (840 mg), triethylamine (0.44 ml) and dimethylformamide (10 ml) were stirred at room temperature for 17 hours. Water was added, extraction was performed with ethyl acetate, NH type silica gel was added to the extract, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (hexane:ethyl acetate=1:1). The solvent was distilled off under reduced pressure to obtain 160 mg of the target substance as a white powder.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH3:8]>CC(C)=O>[I-:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N+:17]([CH3:1])[CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH3:8]
Reactant: CI
Reactant: CCC/C=C\COc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CCC/C=C\COc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 7.5 mmol) and cis-3-(3-(2-hexenyloxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone(4 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:28][CH2:29][CH3:30])=[C:24]([NH2:27])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:31]#[N:32])[CH:12]=[CH:13][C:14]=1[F:15].O.[C:34](=O)(O)[O-].[Na+]>CN1C(=O)CCC1.CC#N>[CH3:30][CH2:29][O:28][C:23]1[CH:22]=[C:21]2[N:20]=[CH:19][C:18]([C:31]#[N:32])=[C:17]([NH:16][C:11]3[CH:12]=[CH:13][C:14]([F:15])=[C:9]([Cl:8])[CH:10]=3)[C:26]2=[CH:25][C:24]=1[NH:27][C:6](/[CH:5]=[CH:4]/[CH2:3][N:2]([CH3:1])[CH3:34])=[O:7]
Reactant: CN1CCCC1=O
Reactant: O=C([O-])O
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)/C=C/CN(C)C
Temperature: 42.5 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A 3 L multi-neck flask was equipped with an agitator, thermometer, dip tube, and nitrogen protection. The flask was charged with N-methyl pyrrolidinone (0.77 kg, 0.75 L, d=1.033 g/mL). At ambient temperature, 4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline (0.0748 kg) ]see, U.S. Pat. No. 6,002,008] was added and the mixture stirred while heating to 40-45° C. and hold for 15 min. The flask was cooled to 0-10° C. The mixture containing 4-N,N-dimethylaminocrotonoyl chloride hydrochloride was transferred via dip tube and positive nitrogen pressure to the 3 L flask over 30-45 min, while maintaining 0-10° C. The mixture was kept at 0-10° C. for a minimum of 2 h. The reaction was checked for completion by HPLC. The reaction is complete when there is ≦2% of the starting material (4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline) present. A 12 L multi-neck flask equipped with agitator, thermometer, dip tube, and nitrogen protection was charged with water (2.61 kg, 2.61 L). Sodium bicarbonate (0.209 kg) was added and stirred until a solution was obtained. The solution was cooled to 20-24° C. The NMP-CH3CN mixture was transferred, via dip tube and positive nitrogen pressure, to the 12 L flask over 45-60 min, while maintaining 20-24° C. The mixture was maintained at 20-24° C. for a minimum of 1 h, and filtered on a Buchner funnel, and rinsed with water (3×0.40 kg, 3×0.40 L) with suction being maintained until dripping stops. The product was dried in a vacuum oven at 50° C. and 10 mm Hg for 28-30 h to give 78.5 g (86% yield) of product.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C@@H:16]2[CH2:21][N:22]2[CH:27]3[CH2:28][CH:29]([OH:31])[CH2:30][CH:23]2[CH2:24][O:25][CH2:26]3)=[N:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[F:34][C:35]([F:66])([F:65])[C:36]([C:42]1[CH:43]=[N:44][C:45]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][C@@H:49]2[CH2:54][N:55]2[CH:60]3[CH2:61][C:62](=[O:64])[CH2:63][CH:56]2[CH2:57][O:58][CH2:59]3)=[N:46][CH:47]=1)([OH:41])[C:37]([F:40])([F:39])[F:38].C(N(CC)CC)C.[Cl:74][C:75]1[N:80]=[CH:79][C:78]([S:81](Cl)(=[O:83])=[O:82])=[CH:77][CH:76]=1>C(Cl)Cl>[Cl:74][C:75]1[N:80]=[CH:79][C:78]([S:81]([N:18]2[CH2:19][CH2:20][N:15]([C:12]3[N:13]=[CH:14][C:9]([C:3]([OH:8])([C:2]([F:1])([F:32])[F:33])[C:4]([F:5])([F:6])[F:7])=[CH:10][N:11]=3)[C@@H:16]([CH2:21][N:22]3[CH:23]4[CH2:30][CH:29]([OH:31])[CH2:28][CH:27]3[CH2:26][O:25][CH2:24]4)[CH2:17]2)(=[O:83])=[O:82])=[CH:77][CH:76]=1.[Cl:74][C:75]1[N:80]=[CH:79][C:78]([S:81]([N:51]2[CH2:52][CH2:53][N:48]([C:45]3[N:46]=[CH:47][C:42]([C:36]([OH:41])([C:35]([F:34])([F:65])[F:66])[C:37]([F:39])([F:38])[F:40])=[CH:43][N:44]=3)[C@@H:49]([CH2:54][N:55]3[CH:56]4[CH2:63][C:62](=[O:64])[CH2:61][CH:60]3[CH2:59][O:58][CH2:57]4)[CH2:50]2)(=[O:83])=[O:82])=[CH:77][CH:76]=1
Reactant: OC1CC2COCC(C1)N2C[C@H]1CNCCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Reactant: O=C1CC2COCC(C1)N2C[C@H]1CNCCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC2COCC(C1)N2C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Product: O=S(=O)(c1ccc(Cl)nc1)N1CCN(c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)[C@@H](CN2C3COCC2CC(O)C3)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 25-mL round-bottomed flask was charged with a 1:1 mixture of 9-(((2R)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2R)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (215 mg, 0.44 mmol), triethylamine (0.19 mL, 1.33 mmol) and CH2Cl2 (5 mL). 6-chloropyridine-3-sulfonyl chloride (94 mg, 0.44 mmol, Organic Process Research & Development 2009, 13, 875) was added as a solution in CH2Cl2 (2 mL) and the reaction was stirred at room temperature for 20 min. The reaction was then concentrated onto silica and purified via column chromatography (12 g silica gel, 0 to 100% EtOAc in hexanes) to give 9-(((2S)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (50 mg).
Reaction SMILES: [C:1]([O:17][CH3:18])(=[O:16])[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:19]([N:26]1[CH2:30]C[CH:28](O)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCCCCCC.[H-].[Na+]>[CH2:19]([N:26]1[CH2:27][CH2:28][CH:18]([O:17][C:1](=[O:16])[C:2]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[OH:3])[CH2:30]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C(O)(c1ccccc1)c1ccccc1
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Product: O=C(OC1CCN(Cc2ccccc2)C1)C(O)(c1ccccc1)c1ccccc1
Yield: 101.5 %

Procedure:
To a solution of 12 g methyl benzilate and 8.2 g 1-benzyl-3-pyrrolidinol in 200 ml n-heptane is added 100 mg sodium hydride and the mixture refluxed for 4 hours, separating the methanol formed in a Dean-Stark separator. The cooled organic phase is washed with water and then extracted with 2N HCl. The aqueous phase is made alkaline with solid K2CO3 and extracted with ether to give 1-benzyl-3-(2,2-diphenyl-2-hydroxyacetoxy)pyrrolidine as an oil (18.2 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1.[K].[S:13]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=1)(=[O:16])(=[O:15])[NH2:14]>CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=[C:2]([NH:14][S:13]([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH:7]=1
Reactant: CCNc1nc(Cl)cc(Cl)n1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Agent: [K]
Solvent: CN1CCCC1=O
Product: CCNc1nc(Cl)cc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)n1
Yield: 70.8 %

Procedure:
2.0 g (0.011 mol) of (4,6-dichloropyrimidin-2-yl)-ethylamine and 5.67 g (0.022 mol) of N-(4-sulfamoyl-phenyl)-acetamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water, the inorganic phase was saturated with sodium chloride and the residual ethyl acetate dissolved in the aqueous phase was distilled off on a rotary evaporator. The aqueous phase was made acid with 1N HCl, the crystals which separated were filtered off under suction and washed with water. After drying there were obtained 2.88 g (75%) of N-[4-(6-chloro-2-ethylamino-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide as beige crystals, which were used directly in the next step.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1>CC1C=CC=CC=1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCN(C(C)=O)CC1
Yield: 82 %

Procedure:
A mixture of 200 parts of acetic acid anhydride, 90 parts of ethyl 4-piperidineacetate and 225 parts of methylbenzene is stirred and refluxed for 3 hours. The reaction mixture is evaporated and the residue is diluted with water. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated, yielding 92 parts (82%) of ethyl 1-acetyl-4-piperidineacetate as a residue.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH2:9]1[NH:8][CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@@H:10]12
Reactant: [H][H]
Reactant: O[C@@H]1C[C@H]2CN(Cc3ccccc3)CCN2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O[C@@H]1C[C@H]2CNCCN2C1

Procedure:
A mixture of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 54D, 1 g, 4.30 mmol) and ethanol (10 mL) were added to 20% palladium hydroxide on carbon, wet (0.100 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude intermediate (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol. To a solution of crude (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol (1.422 g, 10 mmol) and triethylamine (1.62 g, 16 mmol) in dichloromethane (50 mL) was slowly added a solution of 3-(trifluoromethyl)benzoyl chloride (2.09 g, 10 mmol) in dichloromethane (3 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, diluted with ethyl acetate (100 mL), washed with water (20 mL), dried over sodium sulfate, and filtered. The organic solution was concentrated, and the residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.63 (m, 2H), 2.10-2.27 (m, 3H), 2.50 (m, 1H), 2.80-3.00 (m, 2H), 3.20-3.50 (m, 2H), 4.22 (m, 1H), 4.42-4.60 (m, 1H), 4.80 (m, 1H), 7.70 (m, 3H), 7.82 (m, 1H); MS (ESI) m/z 315 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH:12]=[CH:13][C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1.[H][H]>[Ni].CO>[CH3:19][C:17]1([CH3:20])[CH2:16][O:15][C:14]([CH2:13][CH2:12][C:4]2[CH:5]=[C:6]([NH2:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[N:18]1
Reactant: COc1ccc([N+](=O)[O-])cc1C=CC1=NC(C)(C)CO1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COc1ccc(N)cc1CCC1=NC(C)(C)CO1

Procedure:
Raney nickel, 3 g, is added to a solution of 4,5-dihydro-2-[2-(2-methoxy-5-nitrophenyl)ethenyl]-4,4-dimethyloxazole, 10.9 g, in methanol, 500 ml. The mixture is exposed to hydrogen gas until the appropriate quantity of hydrogen is taken up, filtered and the solvent evaporated to give 10.2 g of 3-[2-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)ethyl]-4-methoxybenzenamine as a gum. To an ice cold solution of the previous crude gum and 7 ml of triethylamine in chloroform is added 10.5 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride (U.S. Pat. No. 4,285,951). The mixture is worked up, chromatographed over silica gel and eluted with diethylether to give 10.5 g of N-[3-[2-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)ethyl]-4-methoxyphenyl]-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide as a gum; thin layer chromatography on silica gel: Rf =0.57 (ethyl acetate).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[N:16][OH:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31]Br)[CH2:25]1)=[O:23])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][O:17][N:16]=[C:8]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:25]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: ON=C(Cc1ccccc1)Cc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCON=C(Cc2ccccc2)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.9 %

Procedure:
A mixture of the above oxime (3.0 g, 13 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (4.6 g, 13 mmol), potassium carbonate (5.4 g, 39 mmol) and acetone (40 ml) was stirred at room temperature for 3 days. The mixture was filtered and the solvent was evaporated from the filtrate in vacuo. The residue was purified by column chromatography on silica gel (50 g, cyclohexane/ethyl acetate 3/1) to give 1.8 g of (R)-1-(2-(((1,3-diphenylpropan-2-ylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Br-].C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24](=O)[CH2:25]C>O>[CH2:25]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[CH:24]=[CH2:23]
Reactant: CCC(C)=O
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: C=CCOc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
A reaction mixture obtained by adding 20 g of 4-cyano-4′-hydroxybiphenyl, 20 g of ally bromide and 25 g of potassium carbonate to 250 mL of butanone was refluxed for 7 hours. Water was added to the reaction mixture, which was then separated. An organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain a residue, which was purified by silica gel column chromatography using toluene as an elusion solvent and then subjected to recrystallization from ethanol to obtain 22 g of 4-allyloxy-4′-cyanobiphenyl.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:29])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([O:27][CH3:28])[C:20]([NH:22][Si](C)(C)C)=[O:21])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>O1CCCC1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:29])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([O:27][CH3:28])[C:20]([NH2:22])=[O:21])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CON(CCCCn1c(C)nc2c(N)nc3ccccc3c21)C(=O)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CON(CCCCn1c(C)nc2c(N)nc3ccccc3c21)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.8 %

Procedure:
To a solution of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-methoxy-N′-(trimethylsilyl)urea (4.1 g, 9.9 mmol) in tetrahydrofuran (75 mL) was added 10% aqueous HCl (5 mL). The reaction mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure and the residue was neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with 10% methanol/dichloromethane solution. The organic layer was concentrated under reduced pressure and the crude product was recrystallized twice from methanol. The crystals were dissolved in hot methanol, filtered through a micron filter, and concentrated under reduced pressure to afford a solid that was crystallized from 5% methanol in dichloromethane to yield 0.264 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-methoxyurea as a yellow powder, mp 158-160° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[C:20]([O:24][C:25](=[O:32])[CH:26]([NH2:31])[C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])([CH3:22])[CH3:21]>>[CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:31][CH:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]([O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:32])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C(N)C(C)(C)C
Product: C[C@H](Oc1cc(C(=O)NC(C(=O)OC(C)(C)C)C(C)(C)C)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) and 2-Amino-3,3-dimethyl-butyric acid tert-butyl ester (CAN 99285-38-8) as starting materials and isolated (526 mg, 87%); MS (ESI, m/z): 445.6 (M+H+).