Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:28])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:33])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[NH:14][CH:15]([CH3:28])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:4][CH:3]=2)=[CH:38][CH:37]=1)[CH3:30]
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(C(F)(F)F)c1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3NC(C)CCc3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-methyl-3-(3-trifluoromethyl-phenyl)-propyl]-amine (Enantiomer B) and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:31])[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N:19]1[C:23]([CH2:24]O)=[C:22]([CH3:26])[N:21]=[C:20]1[CH2:27][N:28]([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]1(=[O:61])[NH:55][C:54](=[O:56])[C:53]2=[CH:57][CH:58]=[CH:59][CH:60]=[C:52]12.N(C(OCC)=O)=NC(OCC)=O>>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[CH:11][C:10]([N:19]2[C:23]([CH2:24][N:55]3[C:51](=[O:61])[C:52]4=[CH:60][CH:59]=[CH:58][CH:57]=[C:53]4[C:54]3=[O:56])=[C:22]([CH3:26])[N:21]=[C:20]2[CH2:27][N:28]([CH3:30])[CH3:29])=[C:9]([C:8](=[O:31])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:14]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc(CN(C)C)n(-c2ccc(C(F)(F)F)cc2C(=O)c2ccccc2Cl)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(CN(C)C)n(-c2ccc(C(F)(F)F)cc2C(=O)c2ccccc2Cl)c1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 3, 2'-chloro-5-trifluoromethyl-2-[2-[(dimethylamino)methyl]-4-methyl-5-hyroxymethylimidazol-1-yl]benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[4-trifluoromethyl-2-(o-chlorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:32]1[CH:37]=[CH:36][C:35]([C:38]2([NH2:41])[CH2:40][CH2:39]2)=[CH:34][N:33]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:41][C:38]5([C:35]6[CH:36]=[CH:37][N:32]=[N:33][CH:34]=6)[CH2:40][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: NC1(c2ccnnc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccnnc5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.075 g, 0.186 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamine HCl (0.025 g, 0.185 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.094 g, 0.93 mmol, 5.0 eq) and BOP reagent (0.123 g, 0.278 mmol, 1.5 eq). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. the The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 4% MeOH/CHCl3 as eluent, and further purified the product by prep HPLC. Yield: 0.050 g (52.00%). 1H NMR (400 MHz, CD3OD): δ 9.44 (s, 1 H), 9.15 (d, 1H), 9.11 (s, 1H), 8.02-7.94 (m, 2H), 7.86 (dd, J=2.3, 4.3 Hz, 2H), 7.73 (br s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.40 (dd, J=1.8, 8.5 Hz, 1H), 7.29 (t, J=8.9 Hz, 2H), 2.96 (s, 3H), 2.37 (s, 3H), 1.71 (s, 4H). 19F NMR (376.51 MHz, CD3OD): δ −78.16 (TFA), −113.29 LCMS: (ES+) m/z=521.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)Cl>[C:20]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CCOC(=N)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=NC(C)=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 41 g (22.3 mmol) of ethyl o-chlorobenzimidate and 25 g (25 mmol) of triethylamine in 500 ml of methylene chloride is treated dropwise with 19.5 g (24.8 mmol) of acetyl chloride, the temperature being held at 40° C. by the use of cooling. The reaction mixture is stirred at room temperature for a further 30 minutes, and the mixture is then washed in sequence with water, 5% sodium bicarbonate solution and semi-saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After distillation of the crude product at 110° C./0.16 mmHg (21.33 Pa) there is obtained ethyl N-acetyl-o-chlorobenzimidate as a colourless liquid.
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:67]([NH:69][CH3:70])=[O:68])=[N:53][C:54]([C:57]2[CH:58]=[N:59][N:60]([CH2:63][CH2:64][CH2:65][OH:66])[C:61]=2[CH3:62])=[CH:55][CH:56]=1>>[OH:66][CH2:65][CH2:64][CH2:63][N:60]1[C:61]([CH3:62])=[C:57]([C:54]2[N:53]=[C:52]([C:67](=[O:68])[NH:69][CH3:70])[C:51]([NH:50][C:26]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:25]=3)=[CH:56][CH:55]=2)[CH:58]=[N:59]1
Reactant: CNC(=O)c1nc(-c2cnn(CCCO)c2C)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4C)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 59 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 3-Amino-6-[1-(3-hydroxypropyl)-5-methyl-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 35C, 177 mg, 644 μmol) to afford 270 mg of the title compound (59%). 1H NMR (400 MHz, CD3OD) d 8.59-8.68 (m, 1H), 8.30 (s, 1H), 8.03 (s, 1H), 7.76-7.86 (m, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.01 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 4.26 (t, J=7.1 Hz, 2H), 4.05 (quin, J=7.3 Hz, 4H), 3.88 (s, 3H), 3.53-3.60 (m, 2H), 3.25 (d, J=21.0 Hz, 2H), 2.92-2.98 (m, 3H), 2.63 (s, 3H), 2.04 (t, J=6.7 Hz, 2H), 1.25 (t, J=7.1 Hz, 6H). MS (ESI): m/z=677.21 [M+H]+. UPLC: tR=3.8 min (ZQ3: polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(Cl)(Cl)Cl.[CH3:22][O:23][C:24](Cl)=[O:25]>C(N(CC)CC)C>[CH3:22][O:23][C:24]([NH:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[O:25]
Reactant: Nc1cnc2ccc(Sc3ccccc3)cn12
Reactant: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cnc2ccc(Sc3ccccc3)cn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.0 g. of 3-amino-6-(phenylthio) imidazo [1,2-a] pyridine in 25 ml. of chloroform containing 0.401 g. of triethyl amine is treated dropwise with 0.378 g. of methylchloroformate. The reaction mixture is stirred for 3 hours at room temperature. The chloroform is removed in vacuo and the residue is triturated with water. The solids are collected by filtration, washed well with water and dried. Recrystallization from dimethylformamideethane yields pure 3-(methoxycarbonylamino) 6-(phenylthio) imidazo [1,2-a] pyridine m.p. 211°-215° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].CC([O-])(C)C.[K+].F[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[C:14]([CH3:19])[CH:13]=1>CN(C=O)C>[I:18][C:15]1[CH:16]=[CH:17][C:12]([O:4][CH2:1][CH2:2][CH3:3])=[CH:13][C:14]=1[CH3:19]
Reactant: Cc1cc(F)ccc1I
Reactant: CCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(I)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3.44 mL (45.8 mmol) 1-propanol are added to 3.42 g (30.5 mmol) KOtBu in 18 mL DMF at 0° C. After stirring the solution for 10 min at rt, 1.80 g (7.63 mmol) 4-fluoro-1-iodo-2-methylbenzene are added and the mixture is stirred at 80° C. for 3 h. The reaction is quenched by the addition of sat. aq. NH4Cl solution and extracted with EtOAc (2×). The combined organic layers are washed with sat. aq. NH4Cl solution and brine, dried over sodium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, heptane/EtOAc 9/1).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:26])[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: CCCCCN
Product: CCCCCNCc1ccc(Oc2ccc(C(N)=O)cn2)c(OC)c1
Yield: 67.4 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and amylamine (0.016 g, 0.184 mmol) gives the title compound (0.0426 g, 67.5%) TOF MS ES+ 344.2 (M+H)+, HRMS calcd for C19H26N3O3 344.1974 (M+H)+, found 344.1963, time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.1 min, 100% purity.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[CH:18]([N:13]1[C:12]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH3:29])=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1c2c(nn1C(C)C)CCNCC2
Yield: 61.3 %

Procedure:
The title compound (80 mg) was prepared according to Example 189 using 207 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 198 mg of 2-methylphenylboronic acid. MS (ESI): exact mass calculated for C17H23N3, 269.19; found, m/z 270.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.45-7.40 (m, 2H), 7.36-7.33 (m, 1H), 7.19-7.18 (m, 1H), 4.66 (br s, 2H), 4.10 (m, 1H), 4.00-3.66 (m, 2H), 2.76-2.61 (m, 2H), 2.13 (s, 3H), 1.45-1.29 (m, 6H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH:3]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CC1(O)CC1)OC1CCCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(CC1(O)CC1)OC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(3-hydroxy-2-(tetrahydro-2H-pyran-2-yloxy)propyl)cyclopropanol (1.0 g, 4.63 mmol) and triethylamine (1 mL, 7.4 mmol, Shantou Xilong chemical factory) in 30 mL of CH2Cl2 at 0° C. was added methanesulfonyl chloride (0.64 g, 5.6 mmol, Shanghai Haiqu chemical Ltd.) via a syringe. The reaction mixture was stirred at 0° C. for 1 hr and then quenched with 5 mL of ice-water. The resulted mixture was extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to furnish 3-(1-hydroxycyclopropyl)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate as yellow oil (used in the next step immediately without further purification).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:50][CH2:49][CH2:48][N:47]([CH2:51][C:52]([O:54][CH2:55][C:56]4[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=4)=[O:53])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:50][CH2:49][CH2:48][N:47]([CH2:51][C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=3)=[O:53])[CH2:46][CH2:45]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(CC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15 ml of trifluoroacetic acid and 0.36 ml of trifluoromethanesulfonic acid were added to a solution of 1.47 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(4-nitrobenzyloxycarbonylmethyl)-1-homopiperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 12) in 2.2 ml of anisole, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was treated by a procedure similar to that described in Example 13(1), to give 1.8 g of the title compound as a powder.
Reaction SMILES: [CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][CH:8]=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:19](OCC)=[O:20].[Li+].[BH4-].Cl>C1COCC1>[CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][CH:8]=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:19][OH:20]
Reactant: CCOC(=O)c1ccc2c(ccc3c4ccccc4ccc23)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(ccc3c4ccccc4ccc23)c1
Yield: 94.7 %

Procedure:
Ethyl chrysene-2-carboxylate (20B, 10.1 g, 0.034 mol) in THF (500 mL) was treated with LiBH4 (Alfa, 4×0.5 g, 0.092 mol) under gentle reflux for 4 days. The reaction mixture was poured into ice and acidified carefully to pH 1 with 1M HCl. The precipitate was filtered and recrystallized from THF/hexane to afford 8.32 g (95%) of 2-chrysenemethanol mp 261°-262°, (C, H).
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[N:12]1([C:17]([S-:19])=[S:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.[NH4+].C(O)(=O)C>CO>[N:12]1([C:17]([S:19][CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[S:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: S=C([S-])N1CCCC1
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])CC(SC(=S)N1CCCC1)c1ccccc1
Temperature: 10 °C
Yield: 77 %

Procedure:
β-Nitrostyrene (7.5 grams, 0.050 mole) was added to a cooled (10° C.) stirred slurry of ammonium 1-pyrrolidinecarbodithioate (8.2 grams, 0.050 mole) in methanol (50 ml.). The temperature of the mixture fell to 5° C., then rapidly climbed to 10° C. The cooling bath was removed and the reaction temperature rose slowly to 22° C. Acetic acid (3.0 grams, 0.05 mole) was added, the slurry was cooled to 10° C. and the solid was filtered off, washed with water, and dried in air. The crude product melted at 108° - 116° C. and weighed 11.4 grams (77% yield). Repeated recrystallizations from cool acetone-methanol, hot acetone-2-propanol, and cool methylene chloride-toluene-hexane solutions gave pure α-(nitromethyl)benzyl 1-pyrrolidinecarbodithioate melting at 116° - 120° C. (sintering at 113° C.).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[N:31][CH:32]=[N:33][CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cncnc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cncnc2)CC1
Yield: 8 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), pyrimidine-5-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless solid (8%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](=[NH:10])[N:7]([CH2:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](O)=[O:24]>>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:23](=[O:24])[C:22]2[CH:26]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=2[O:27][CH3:28])/[N:7]([CH2:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cn(C[C@@H]2CCCO2)c(=N)s1
Reactant: COc1ccc(Cl)cc1C(=O)O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@@H]1CCCO1

Procedure:
The products from Example 315A and 5-chloro-2-methoxy-benzoic acid were processed using the method described in Example 300 to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (s, 9H), 1.62-1.95 (m, 3H), 2.00-2.12 (m, 1H), 3.72-3.87 (m, 2H), 3.90 (s, 3H), 4.18-4.34 (m, 2H), 4.42 (dd, J=12.0, 2.4 Hz, 1H), 6.86 (s, 1H), 6.90 (d, J=8.8 Hz, 1H), 7.32 (dd, J=8.8, 2.7 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H). MS (ESI+) m/z 409 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33].C(OCC)(=O)C>CN(C)C=O>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)=[N:8][N:7]4[C:2]([N:32]([CH3:33])[CH3:31])=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1cccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(-c2nn3c(N(C)C)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 100 °C
Yield: 70 %

Procedure:
To a solution of 4-[7-chloro-2-(3-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (60 mg, 0.14 mmol) in N,N-dimethylformamide (10 mL) was added dimethylamine (7 mL 40% in water). The solution was heated in a steal bomb at 100° C. for 3 days. The bomb was cooled to room temperature and ethyl acetate was added to the reaction mixture. The organics were washed with water, brine and dried over magnesium sulfate. Filtration and concentration followed by purification with flash chromatography (95:5-dichloromethane: methanol) gave 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(3-methoxyphenyl)-N,N-dimethylpyrazolo[1,5-a]pyridin-7-amine (43 mg, 70%) as a yellow foam. 1H NMR (CDCl3) δ 8.11 (d, 1H), 7.95 (s, 1H), 7.35–7.30 (m, 2H), 7.24–7.21 (m, 2H), 6.97 (dd, 1H), 6.36 (d, 1H), 6.32 (d, 1H), 5.40 (broad s, 1H), 4.37 (m, 1H), 3.80 (s, 3H), 3.12 (s, 6H), 2.11–2.06 (m, 2H), 1.77–1.56 (m, 6H); MS m/z 429.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11].C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1(C)C=CC=CC=1>[F:8][C:4]1[N:3]=[C:2]([C:10]([CH3:12])([CH3:11])[C:9]#[N:13])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C#N
Reactant: Fc1cccc(F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a 0° C. solution of 2,6-difluoropyridine (69.6 g, 605 mmol, 1.0 equiv) and isobutyronitrile (41.7 g, 610 mmol, 1.0 equiv) in toluene (500 mL) was added sodium hexamethyldisilazide (2.0 M in THF, 302 mL, 605 mmol, 1.0 equiv) in a dropwise manner. The resulting mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction was then quenched with water (500 mL), and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (2×300 mL), and the combined organic phases were washed with saturated brine solution (2×400 mL), dried over Na2SO4, concentrated to give a crude yellow oil, and chromatographed with silica gel (2-10% EtOAc/hex) to give 2-(6-fluoropyridin-2-yl)-2-methylpropanenitrile (55.7 g, 56%) as a clear oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=C)=[CH:18][CH:17]=4)=[C:7]([C:26]([F:29])([F:28])[F:27])[CH:6]=1)([CH3:3])[CH3:2].C[N+]1([O-])CC[O:34]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:34])=[CH:18][CH:17]=4)=[C:7]([C:26]([F:28])([F:27])[F:29])[CH:6]=1)([CH3:2])[CH3:3]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)cc1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.2 %

Procedure:
To 3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 17B, 0.225 g, 0.563 mmol) in THF (2 mL) was added N-methylmorpholine-N-oxide (50% in water) (0.3 mL, 0.563 mmol) followed by osmium tetroxide (4% in water) (0.088 mL, 0.011 mmol) at room temperature. The contents were stirred at room temperature for 14 h. Sodium periodate (0.181 g, 0.845 mmol) dissolved in 1 mL of water was added at room temperature. The contents were stirred at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate (10 mL) and brine (5 mL). The dichloromethane layer was dried over sodium sulfate and concentrated to yield 3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.222 g, 0.553 mmol, 98% yield). LC/MS M+1=402.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Fc1ccc(C2CCCN2)cc1F
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccc(F)c(F)c1

Procedure:
The title compound, white solid, m.p. 121° C. and MS: m/e=358.1 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(3,4-difluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.