Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([NH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C@H:2]1[C@@H:7]([NH:8][C:9](=[O:10])[O:11][CH3:12])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: COC(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H]1CCNC[C@H]1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 140 %

Procedure:
(3R,4S)-tert-butyl 3-fluoro-4-((methoxycarbonyl)amino)piperidine-1-carboxylate (127 mg, 0.460 mmol) was taken up in DCM (5 mL) and TFA (0.708 mL, 9.19 mmol) was added. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the material was dissolved in MeOH. The solution was loaded onto an SCX column (5 g, benzenesulfonic acid sorbent) and the column was rinsed with MeOH, followed by 7N NH3/MeOH to obtain the product. The solvent was removed in vacuo to obtain methyl ((3R,4S)-3-fluoropiperidin-4-yl)carbamate (113.5 mg) as a colorless gum. The crude material was taken onto the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:25][CH2:26][CH3:27])[C:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:10]2[C:9]2[CH:8]=[CH:7]C=[CH:5][C:4]=2[N:3]=1.C(OC([NH:35]C1C=NC=CC=1B(O)O)=O)(C)(C)C>>[NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:25][CH2:26][CH3:27])[C:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[C:10]2[C:9]2[CH:8]=[CH:7][N:35]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1cnccc1B(O)O
Product: CCCn1nc2c(N)nc3cnccc3c2c1CCNC(=O)OC(C)(C)C
Yield: 20.4 %

Procedure:
A modification of the method described in Example 610 was used to couple tert-butyl 2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethylcarbamate (2.08 g, 5.82 mmol) (Example 51, Parts A through G) with 3-[(tert-butoxycarbonyl)amino]pyridin-4-ylboronic acid (2.77 g, 11.6 mmol). After the first purification by IFC, 0.44 g of tert-butyl 2-(4-amino-2-propyl-2H-pyrazolo[3,4-c][1,7]naphthyridin-1-yl)ethylcarbamate was obtained as a yellow solid.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C@@H:10]([O:15][CH2:16][C:17]2[C:18]([NH2:32])=[N:19][C:20](=[O:31])[N:21]([CH:30]=2)[C@@H:22]2[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[CH2:23]2)[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:33]([O-:35])=[O:34])[CH:3]=1.[CH2:36]([N-:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[C:37]#[CH:38].CCN(CC)CC>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:9][O:8][C:7]1[C:2]([C:38]#[C:37][CH2:36][NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])=[CH:3][C:4]([N+:33]([O-:35])=[O:34])=[C:5]([C@@H:10]([O:15][CH2:16][C:17]2[C:18]([NH2:32])=[N:19][C:20](=[O:31])[N:21]([CH:30]=2)[C@@H:22]2[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[CH2:23]2)[C:11]([CH3:13])([CH3:14])[CH3:12])[CH:6]=1
Reactant: COc1cc([C@@H](OCc2cn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)nc2N)C(C)(C)C)c([N+](=O)[O-])cc1I
Reactant: C#CC[N-]C(=O)C(F)(F)F
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc([C@@H](OCc2cn([C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)nc2N)C(C)(C)C)c([N+](=O)[O-])cc1C#CCNC(=O)C(F)(F)F
Yield: 91.6 %

Procedure:
A solution of compound 66 (245 mg, 0.4 mmol), N-propargyltrifluoroacetylamide (603 mg, 4.0 mmol), tetrakis(triphenylphosphine)-palladium(0) (92 mg, 0.8 mmol), CuI (30 mg, 0.16 mmol), and Et3N (240 μL, 1.7 mmol) in anhydrous DMF (5.0 mL) was stirred at 50° C. for 12 hours. The mixture was concentrated in vacuo and purified by silica gel column chromatography to yield 5-{(S)-1-[5-methoxy-4-(3-trifluoroacetamido-1-propynyl)-2-nitrophenyl]-2,2-dimethyl-propyloxy}methyl-2′-deoxycytidine 67 (230 mg, 91%). 1H NMR (400 MHz, MeOD-d4): δ 7.98 (s, 1H, Ph-H), 7.92 (s, 1H, H-6), 7.19 (s, 1H, Ph-H), 6.15 (t, 1H, J=6.4 Hz, H-1′), 5.21 (s, 1H, Ph-CH), 4.41 (d, 1H, J=13.2 Hz, 5-CH2a), 4.33 (m, 3H, H-3′ and CH2), 4.27 (d, 1H, J=13.2 Hz, 5-CH2b), 3.96 (s, 3H, OCH3), 3.88 (m, 1H, H-4′), 3.72 (m, 2H, H-5′), 2.30 (m, 1H, H-2′a), 2.12 (m, 1H, H-2′b), 0.84 (s, 9H, C(CH3)3).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:23]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C@H:24]([C:40]([NH:42][C@H:43]([C:56](O)=[O:57])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:23]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C@H:24]([C:40]([NH:42][C@H:43]([C:56]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:57])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1
Yield: 67.6 %

Procedure:
compound SP307P. Same procedure as above with Trp-NHCH2Ph (120.7 mg, 0.411 mmol), N-Boc-Tyr(Bn)-Lys(Boc)-OH (246.9 mg, 0.411 mmol), EDC (87.1 mg, 0.45 mmol) and HOBt (62.1 mg, 0.46 mmol) in CH2Cl2/DMF (1.8 mL, 1/1). The crude residue was triturated with MeOH/pentane to afford a white solid (243 mg, 67%). 1H NMR (300 MHz, DMSO-d6) δ 1.2-1.61 (m, 6H, 3 CH2 Lys), 1.29 (s, 9H, (CH3)3), 1.36 (s, 9H, (CH3)3), 2.64 (m, 1H, CH2 Tyr), 2.86 (m, 3H, CH2 Lys, CH2 Tyr), 3 (dd, J=14.1 Hz, J=7 Hz, 1H, CH2 Trp), 3.14 (dd, J=14.1 Hz, J=6 Hz, 1H, CH2 Trp), 4.11 (m, 1H, CHα), 4.26 (m, 3H, CH2 (Bn Trp), CHα), 4.59 (m, 1H, CHα), 5.02 (broad s, 2H, CH2 (Bn)), 6.72 (m, 1H), 6.85-7.4 (m, 19H), 7.59 (d, J=7.6 Hz, 1H), 7.89 (d, J=7.4 Hz, 1H), 8.1 (d, J=7.4 Hz, 1H), 8.38 (m, 1H), 10.8 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 22.4, 29.2, 32 (3 CH2 Lys), 27.8 (CH2 Trp), 28.1, 28.2 (2 (CH3)3), 36.3 (CH2 Tyr), 39.8 (CH2 Lys), 42 (CH2 (Bn) Trp), 52.4, 53.5, 55.8 (CHα Tyr, Lys, Trp), 69.1 (CH2 (Bn)), 77.3, 78 (2 C(CH3)3), 109.7, 111.2, 114.3, 118.2, 118.4, 120.8, 123.5, 126.5, 126.9, 127.3, 127.5, 127.7, 128, 128.3, 130.1, 130.2, 136, 137.2, 139 (25 aromatic C), 155.2, 155.5, 156.8 (Car-O, 2 CO carbamate), 171, 171.3, 171.6 (3 CO amide). Anal. Calcd. for C50H62N6O, 2H2O: C, 65.91; H, 7.30; N, 9.22. Found: C, 65.59; H, 7.06; N, 9.09.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11]C1C2C(=CC=CC=2)NC=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11]
Reactant: Cc1c[nH]c2ccccc12
Reactant: Clc1cccc2[nH]ccc12
Product: Cn1ccc2c(Cl)cccc21
Yield: 100 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 4-chloroindole for the 3-methylindole, the title compound (2.2 g, 100%) was obtained as an amber oil: MS (ES) m/e 166.0 (M+H)+.
Reaction SMILES: I[CH3:2].[Si:3]([O:10][CH2:11][C:12]1[C:13]2[N:14]([N:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[C:15]([CH2:18][OH:19])=[CH:16][CH:17]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C(#N)C.[Ag]=O>[Si:3]([O:10][CH2:11][C:12]1[C:13]2[N:14]([N:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=2)[C:15]([CH2:18][O:19][CH3:2])=[CH:16][CH:17]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CO)n2nc(C(F)(F)F)cc12
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: COCc1ccc(CO[Si](C)(C)C(C)(C)C)c2cc(C(F)(F)F)nn12
Temperature: 25 °C
Reaction time: 85 h

Procedure:
Silver oxide (30.0 g) and iodomethane (16.1 mL) were added to a solution of the compound of Example 324 (9.53 g) in acetonitrile (300 mL). The mixture was stirred at room temperature for 85 hours. Subsequently, the mixture was filtered through Celite. The filtrate was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to afford the title compound as a pale yellow powder (8.76 g).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([O:15][CH2:16][CH2:17]Br)=[O:14])=[O:8])(=[O:3])[CH3:2].N1C=CC=C(C(N)=[O:36])C=1>CO>[C:1]([S:4][CH2:5][CH:6]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([O:15][CH2:16][CH2:17][OH:36])=[O:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCCBr)c1
Reactant: NC(=O)c1cccnc1
Solvent: CO
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)OCCO)c1
Yield: 55.1 %

Procedure:
2-Bromoethyl 3-[(2-acetylthiomethyl-3-phenylpropionyl)amino]benzoate (compound of Example 123) (0.63 g) and 3-pyridinecarboxamide (0.17 g) are dissolved in methanol (10 ml), and the mixture is refluxed overnight. Methanol is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. Ethyl acetate is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with silica gel (eluant, chloroform). The fractions containing the desired compound are collected, and chloroform is distilled off under reduced pressure to give the title compound (0.3 g) as an oily substance. IR (film; cm-1): 1715, 1685, 1660 Mass spectrum (SIMS) [M+H]+ : m/z 402
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[CH3:21][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([OH:20])=[O:19]
Reactant: CC(C)(C)CCBr
Reactant: CC(C(=O)O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)CCC(C)(C(=O)O)c1ccccc1
Reaction time: 17 h
Yield: 95.5 %

Procedure:
Lithium bis(trimethylsilyl)amide (32.3 g, 193 mmol) was added to 80 mL of tetrahydrofuran and the resulting solution was cooled in an ice bath. Addition of a solution of 2-phenyl-propionic acid (11.6 g, 77.3 mmol) in 10 mL of tetrahydrofuran to the reaction solution was followed by addition of 1-bromo-3,3-dimethyl-butane (20.4 g, 124 mmol). The reaction vessel was removed from the cooling bath, placed in a 50° C. oil bath, and the reaction solution was stirred for 17 hours. After concentration, the resulting residue was dissolved in 250 mL of 1 N NaOH, washed with 250 mL of 2:1 hexane/iso-propyl acetate, acidified to pH 1 with 6 N HCl, and extracted with ethyl acetate (3×300 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 17.3 g (96%) of clear oil. 1H NMR (300 MHz, CDCl3): δ ppm 0.86 (s, 9H) 1.09 (m, 2H) 1.56 (s, 3H) 1.99 (m, 2H) 7.33 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:21][CH:20]=1)[C:13]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][CH:31]=1)=[C:12]2[CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[K+].[NH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)=[CH:21][CH:20]=1)[C:13]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][CH:31]=1)=[C:12]2[CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCCCl)cc2)c2ccc(OCc3ccccc3)cc12
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12

Procedure:
A solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-chloro-propoxy)-benzyl]-3-methyl-1H-indole No. 164 (3 g, 5.1 mmol), potassium iodide (2.5 g, 15.3 mmol) and piperidine (3.0 mL, 30.6 mmol) were heated in DMF (30 mL) at 100° C. for 18 hours. The reaction was worked up by pouring into water and extracting with ethyl acetate. The organic layer was washed with water, brine and dried over magnesium sulfate. The solution was concentrated to an oil and the product precipitated out by adding methanol. The product was obtained as a white solid: Mp=104-106° C.; 1H NMR (DMSO) 7.47 (d, 4H, J=7.5 Hz), 7.38 (q, 4H, J=7.9 Hz), 7.36-7.30 (m, 1H), 7.28 (d, 2H, J=8.3 Hz), 7.19 (d, 1H, J=8.8 Hz), 7.12-7.10 (m, 4H), 6.80 (dd, 1H, J=8.8, 2.0 Hz), 6.72 (s, 4H), 5.14 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 3.86 (t, 2H, J=6.4 Hz), 2.35-2.20 (m, 6H), 2.14 (s, 3H), 1.78-1.75 (m, 2H), 1.47-1.42 (m, 4H), 1.40-1.31 (m, 2H); MS eI m/z 650.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:14]3[C@H:9]([CH2:10][CH2:11][NH:12][CH2:13]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1.[CH2:17](Br)[CH3:18]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:14]3[C@H:9]([CH2:10][CH2:11][N:12]([CH2:17][CH3:18])[CH2:13]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: O=C1C[C@H]2CCNC[C@H]2c2ccc(F)cc21
Reactant: CCBr
Product: CCN1CC[C@@H]2CC(=O)c3cc(F)ccc3[C@@H]2C1

Procedure:
In an analogous manner to that described in Example 49 b), from cis-8-fluoro-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one by alkylation with ethyl bromide there was obtained cis-8-fluoro-2-ethyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one, which was converted with MeOH/HCl into the hydrochloride with m.p. >220°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>C(N(CC)CC)C.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][C:20]([OH:24])([C:22]#[C:23][C:12]1[C:13]2[C:4]([N:5]=[C:6]3[C:11]=1[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=[CH:7]3)=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)[CH3:21]
Reactant: C#CC(C)(C)O
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2nc3cc(Cl)ccc3c(C#CC(C)(C)O)c2c1

Procedure:
A mixture of 6,9dichloro-2-methoxyacridine (3.5 g, 12.6 mmol), 2-methyl-3-butyn-2-ol (1.27 g, 15 mmol), dichlorobis(triphenylphosphine)palladium (100 mg), and cuprous iodide (25 mg) in triethylamine (35 mL) and dimethylformamide (20 mL) was heated at 90° for 12 h. The mixture was cooled and diluted with aqueous potassium carbonate to give the title compound. MS(ES) m/e 326.2 (M+H)+.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.Cl[C:25]1C=CC=C(C(OO)=O)C=1.[S:35](=[O:38])(O)[O-:36].[Na+]>C(Cl)Cl>[CH3:25][S:35]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1)(=[O:38])=[O:36]
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 25 mL round bottom flask fitted with a stir bar was added 2-methylthio-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (Reference Example 3) (762 mg, 2 mmol) and 10 mL DCM. The flask was cooled to 0° and a slight excess of m-chloroperbenzoic acid (70%) (1.0 g, 4 mmol) was slowly added and stirred overnight at room temperature. The reaction was worked up by adding 1.0M sodium bisulfite (3 mL), 25 mL more of DCM and the reaction was stirred vigorously to destroy any excess peracid. After washing with 1.0 M sodium bicarbonate, the DCM layer was dried over MgSO4. Filtering the mixture and reducing the solvent volume under reduced pressure gave the desired product which was 97% pure by LC. This was used without further purification. HPLC/MS: m/e=415 (M+); Rt=3.68 min; 1H-NMR 500 MHz (CDCl3): δ 3.46 (s, 3H), 7.08 (d, J=9 Hz, 2H), 7.31-7.4 (m, 5H), 9.00 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15]>C(Cl)Cl>[CH3:1][N:2]([CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:3]
Reactant: COC(=O)c1cc(F)cc(CBr)c1
Reactant: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cc(F)cc(CN(C)C)c1
Reaction time: 2 h

Procedure:
To a solution of 2.0M dimethylamine in THF (3.24 mL, 6.48 mmol) was added methylene chloride (2 mL) and methyl 3-(bromomethyl)-5-fluorobenzoate (0.200 g, 0.810 mmol from Step 2). The reaction was heated in a sealed reaction vessel in an oil bath held at 60° C. for 2 hours. Solvent and excess reagent were removed in vacuo and the residue was subjected to flash chromatography, eluting with a gradient from 0-20% MeOH in DCM containing some NH4OH (50 mg, 29%). 1H NMR (300 MHz, CDCl3): δ 7.80-7.77 (m, 1H), 7.62 (ddd, 1H), 7.29 (ddd, 1H), 3.90 (s, 3H), 3.53 (s, 2H), 2.29 (s, 6H); 19F NMR (282 MHz, CDCl3): δ−113.10 (t, 1F); LCMS (M+H)+: 212.1.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7](Cl)[CH:6]=1)=[O:4].Cl.[NH2:18][C@H:19]1[CH2:23][CH2:22][N:21]([C:24](=[O:37])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[CH2:20]1.C(N(CC)CC)C.C(O)(C)C>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:16])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24](=[O:37])[CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][CH:31]=3)[CH2:20]2)[CH:6]=1)=[O:4]
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: CN(C)C(=O)c1cc(Cl)nc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1cc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)nc2ccccc12
Temperature: 130 °C
Yield: 18.5 %

Procedure:
A mixture of 2-chloroquinoline-4-carboxylic acid dimethylamide (0.20 g), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.13 g), triethylamine (95 mg), and isopropanol (0.85 mL) was heated at 130° C. in a microwave reaction apparatus for 1.5 h. The reaction mixture was diluted with chloroform, washed with 1 M aqueous sodium hydroxide, and then dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=1:3−ethyl acetate) to obtain 2-((S)-1-(2-(4-trifluoromethoxyphenyl)ethanoyl)pyrrolidin-3-ylamino)quinoline-4-carboxylic acid dimethylamide (36 mg). (2) 2-((S)-1-(2-(4-Trifluoromethoxyphenyl)ethanoyl)pyrrolidin-3-ylamino)quinoline-4-carboxylic acid dimethylamide (36 mg) was dissolved in ethyl acetate, followed by addition of a solution (0.046 mL) of 4 M HCl in ethyl acetate. The mixture was concentrated under reduced pressure, and then the resulting residue was solidified with a mixed solvent of diisopropyl ether and chloroform to obtain the title compound (21 mg).
Reaction SMILES: C([Li])(C)(C)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][N:8]=1.CN(C)[CH:19]=[O:20].[NH4+].[Cl-]>CCCCC.C(OCC)C>[Cl:6][C:7]1[CH:12]=[C:11]([C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][N:8]=1)[CH:19]=[O:20]
Reactant: COCOc1ccc(Cl)nc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCC
Product: COCOc1cnc(Cl)cc1C=O
Temperature: -76 °C
Reaction time: 0.33 h

Procedure:
tert-Butyllithium in pentane (1.7 M, 19.0 mL) was added dropwise to a solution of 2-chloro-5-(methoxymethoxy)pyridine (4.880 g, 28.11 mmol) in 100 ml of ethyl ether at −76° C. Some precipitate appeared. The mixture was kept at −76° C. for 20 min then N,N-dimethylformamide (2.938 mL, 37.95 mmol) was added dropwise. The mixture was stirred for 10 min at −76° C. and then allowed to warm to at 0° C. for 1 h period. 10% aq NH4Cl was added and the mixture was extracted with ethyl acetate. The organic solution was washed with water, brine and dried over Na2SO4. After concentration in vacuum the yield of the crude 2-chloro-5-(methoxymethoxy)isonicotinaldehyde 5.49 g. MS: 202.0, 172.0. Without further purification was used in the next step.
Reaction SMILES: N1C2NC=CC=2C=NC=1.[Cl:10][C:11]1[C:12]2[C:19](I)=[CH:18][N:17]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)[C:13]=2[N:14]=[CH:15][N:16]=1.[O:34]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(#N)C>[Cl:10][C:11]1[C:12]2[C:19]([C:44]3[CH:45]=[CH:46][C:41]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:42][CH:43]=3)=[CH:18][N:17]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: CN1CCC(N2CCC(n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ncc2cc[nH]c2n1
Solvent: CC#N
Solvent: COCCOC
Solvent: O
Product: CN1CCC(N2CCC(n3cc(-c4ccc(Oc5ccccc5)cc4)c4c(Cl)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
1H NMR (DMSO-d6, 400 MHz) 8.62(s, 1H), 8.16(s, 1H), 4.66-4.58(m, 1H), 3.17(s, 1H), 3.02-3.00(d, 2H, J=8 Hz), 2.84-2.82 (d, 2H, J=8 Hz), 2.33-2.26(m, 2H), 2.17 (s, 3H), 2.08-2.04(m, 2H), 1.95-1.85 (m, 4H), 1.91-1.88(d, 2H, J=12 Hz), 1.49-1.45(m, 2H); Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 3.505 min. 4-chloro-5-(4-phenoxyphenyl)-7-1-(1-methyl-4-piperidinyl)-4-piperidinyl]-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4-chloro-5-iodo-7-[ 1-(1-methyl-4-piperidinyl)-4-piperidinyl]-7H-pyrrolo[2,3-d]pyrimidine (0.390 g, 0.845 mmol), 4-phenoxyphenyl boronic acid (0.199 g, 0.93 mmol), tetrakis(triphenylphosphine)pallidium (0.058 g, 0.051 mmol), and sodium carbonate (0.215 g, 2.03 mmol) were heated in a mixture of ethylene glycol dimethyl ether (20 mL) and water (10 mL) at 80° C. for 7 hours under a nitrogen atmosphere. Reaction solution was allowed to cool to room temperature, and the organic layer was removed under reduced pressure. Ethyl acetate was added, the layers were partitioned and the aqueous layer was extracted with ethyl acetate (250 mL). The organic layers were combined, washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica using 10% methanol in dichloromethane, then 20% methanol in dichloromethane as eluent to give 0.241 g (51%) of 4-chloro-5-(4-phenoxyphenyl)-7-[1-(1-methyl-4-piperidinyl)-4-piperidinyl]-7H-pyrrolo[2,3-d]pyrimidine.