Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].N1C=CC=CC=1.[H][H]>[Pd].O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: [H][H]
Reactant: CCCCCC#CCC#CCC#CCCCCCCCl
Agent: [Pd]
Solvent: O
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCCCl

Procedure:
A mixture of 35.9 g. of 1-chloro-7,10,13-nonadecatriyne dissolved in 200 ml. of pyridine and 5.4 g. of 5% palladium on barium sulfate was shaken in an atmosphere of hydrogen in a Parr hydrogenator for 1.25 hrs. (pressure drop 21.5 lb.; 0.1 mole hydrogen = 8.5 lb.), then the reaction mixture was poured into water and extracted with ether. The ether extract was washed several times with water, then with dilute hydrochloric acid, followed by saturated aqueous sodium chloride. The ether solution was then dried over sodium sulfate, and evaporated under reduced pressure leaving a residue comprising 1-chloro-cis,cis,cis-7,10,13-nonadecatriene which was further purified by distillation on a shaking short path distillation apparatus, giving 27 g. of 1-chloro-cis,cis,cis-7,10,13--nonadecatriene collected at a jacket temperature of 180°-190°/0.005 mm.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](F)=[O:20])=[N:17][CH:18]=1>O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([O:4][CH:2]([CH3:3])[CH3:1])=[O:20])=[N:17][CH:18]=1
Reactant: O=C(F)c1ccc(F)cn1
Reactant: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine (0.405 g, 4 mmol) were added drop-wise at room temperature to the 5-fluoropicolinoyl fluoride provided above. The mixture was stirred at room temperature overnight, poured into a reparatory funnel with water and extracted with ethyl ether. The organic phase was then washed with water and dried over MgSO4. The solvent was removed with a rotary evaporator. The concentrated crude product was purified using column chromatography (silica gel) with ethyl acetate/hexanes mixture (1/10) as eluent to give 0.17 g (23% yield, 96% LC purity) of desired product as an off-white solid. GC/MS results were consistent with the chemical formula of isopropyl 5-fluoropicolinate: 70 eV EIMS (GC) m/z=142 (43%), 124 (100%), 97 (97%), 96 (93%), 43 (59%). 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=2.8 Hz, 1H), 8.18 (dd, J=8.8, 4.4 Hz, 1H), 7.52 (ddd, J=8.7, 7.9, 2.9 Hz, 1H), 5.34 (hept, J=6.3 Hz, 1H), 1.43 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 163.63 (s), 162.32 (s), 159.71 (s), 144.84 (d, J=3.8 Hz), 138.46 (d, J=24.8 Hz), 126.78 (d, J=5.4 Hz), 123.31 (d, J=18.5 Hz), 69.71 (s), 21.81 (s). 19F NMR (376 MHz, CDCl3) δ −120.51.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:10]([C:11]3[CH:16]=[C:15]([CH2:17][N:18]([CH3:20])[CH3:19])[N:14]=[C:13]([NH:21][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1>C1(N)CCCC1.C(OCC)(=O)C>[CH:22]1([NH:21][C:2]2[N:7]3[N:8]=[C:9]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:10]([C:11]4[CH:16]=[C:15]([CH2:17][N:18]([CH3:20])[CH3:19])[N:14]=[C:13]([NH:21][CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[N:12]=4)=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CN(C)Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Agent: NC1CCCC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(NC4CCCC4)cccc23)nc(NC2CCCC2)n1
Temperature: 100 °C
Yield: 30 %

Procedure:
A solution of 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-[(dimethylamino)methyl]-2-pyrimidinamine (60 mg, 0.13 mmol) in cyclopentylamine (2 mL) was heated in a sealed tube at 95° C. for 16 hours followed by heating at 100° C. for 72 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was concentrated and chromatographed (37:3 dichloromethane:methanol) to provide N-cyclopentyl-3-{2-(cyclopentylamino)-6-[(dimethylamino)methyl]-4-pyrimidinyl}-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (10 mg, 15%). 1H NMR (CDCl3) δ 7.70 (d, 1H), 7.65 (m, 2H), 7.31 (t, 1H), 7.12 (t, 2H), 6.37 (s, 1H), 6.05–5.95 (m, 2H), 5.13 (d, 1H), 4.35 (m, 1H), 4.01 (m, 1H), 3.20 (s, 2H), 2.20 (s, 6H), 2.15 (m, 2H), 2.05 (m, 2H), 1.90–1.50 (m, 12H); MS m/z 514 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[C:29]([CH:30]([F:41])[C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[C:28]([CH:42]4[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44][CH2:43]4)[C:27]4[CH:26]([O:50]CC5C=CC(OC)=CC=5)[CH2:25][C:24]([CH3:61])([CH3:60])[CH2:23][C:22]=4[N:21]=3)[CH2:16][CH2:15]2)=[N:12][CH:13]=1>>[F:49][C:45]1([F:48])[CH2:46][CH2:47][CH:42]([C:28]2[C:27]3[CH:26]([OH:50])[CH2:25][C:24]([CH3:61])([CH3:60])[CH2:23][C:22]=3[N:21]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:11]4[N:10]=[CH:9][C:8]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:13][N:12]=4)[CH2:15][CH2:16]3)[C:29]=2[CH:30]([F:41])[C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:38])[F:40])=[CH:35][CH:36]=2)[CH2:43][CH2:44]1
Reactant: C1CCNCC1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(N5CCCCC5)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of the first step of Example 5 and Example 7 were performed except for using piperidine instead of morpholine, and from 100 mg (0.120 mmol) of (−)-2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 11, 41 mg of the title compound was obtained as a light brown solid (yield: 48%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6](=O)([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.II.C(P(CCCC)CCCC)CCC>C(#N)C.C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=P(c1ccco1)(c1ccco1)c1ccco1
Agent: CCCCP(CCCC)CCCC
Agent: II
Solvent: C1CCOC1
Solvent: CC#N
Product: c1coc(P(c2ccco2)c2ccco2)c1

Procedure:
100 mg (0.431 mmol) of tri(2-furyl)phosphine oxide (31P NMR, s, −15.4) were treated with I2 11 mg (43 μmol) and tributylphosphine 180 μL (0.70 mmol) in acetonitrile/THF (1:1 v/v) 2 mL for 19 hours at room temperature, which gave 31P NMR integrated conversion of tri(2-furyl)phosphine (31P NMR, s, −76.5) in ca. 50%.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]4)[CH:19]=3)[CH:14]=2)[CH2:7]1)=[O:5])C.C(O)C.[OH-].[Na+].Cl>>[C:30]([C@H:27]1[CH2:28][CH2:29][C@H:24]([O:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:22]=[CH:21]3)[CH2:25][CH2:26]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)[C@@H]1CCCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN4CCC[C@@H](C(=O)O)C4)ccc3c2)CC1
Reaction time: 18 h

Procedure:
(R)-1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-piperidine-3-carboxylic acid ethyl ester (363.4 mg, 0.8046 mmol) was dissolved in ethanol (5 mL, 80 mmol) then treated with 1 M aqueous sodium hydroxide (5 mL, 5 mmol). The mixture was stirred vigorously for 18 hours. pH was adjusted to 3-4 with 3 N HCl and reaction was then extracted three times with ethyl acetate. Organics were combined then dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Ethyl ether was then added and a white precipitate formed which was removed via filtration to give a white solid that 86% pure by HPLC. The process was repeated two additional times to give the title compound as a white solid (156 mg, 44%). EDI-MS: 424.2 (M+H)+. 1H NMR (400 MHz, MeOD) δ=7.82 (s, 1H), 7.74-7.62 (m, 2H), 7.42 (d, J=2.3, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.08 (d, J=2.5, 1H), 4.43-4.34 (m, 1H), 4.33-4.22 (m, 2H), 2.71 (br. s., 1H), 2.16 (d, J=2.0 Hz, 2H), 1.88-167 (m, 4H), 1.40-1.25 (m, 3H), 1.24-1.11 (m, 4H), 1.10-0.95 (m, 5H), 0.79 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12].[H-].[Na+].F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1cc2c(Cl)cc(O)cc2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cc(Oc3ccccc3[N+](=O)[O-])cc2n1C
Temperature: 25 °C
Yield: 86.2 %

Procedure:
After 0.42 g (1.64 mmol) of ethyl 4-chloro-6-hydroxy-1-methyl-2-indolecarboxylate was added to a suspension of 0.066 g (1.64 mmol) of 60% sodium hydride and 5 ml of dimethylformamide, the suspension was stirred at room temperature until the mixture became an almost transparent solution. Then 0.35 g (2.49 mmol) of 1-fluoro-2-nitrobenzene was added to the solution at room temperature followed by stirring for 5 hours at the same temperature. The reaction mixture was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate. The combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was isolated and purified by silica gel column chromatography to give 0.53 g (94.3%) of ethyl 4-chloro-1-methyl-6-(2-nitrophenoxy)-2-indolecarboxylate.
Reaction SMILES: NC(N)=S.[CH3:5][N:6]([CH3:19])[S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:18])(=[O:9])=[O:8].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[S:30]>>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([F:20])([F:31])[F:32])=[S:30])=[C:11]([OH:18])[C:10]=1[S:7]([N:6]([CH3:19])[CH3:5])(=[O:9])=[O:8]
Reactant: FC(F)(F)c1ccccc1N=C=S
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=S
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2C(F)(F)F)c1O
Yield: 51.7 %

Procedure:
Following the general procedure for thiourea formation outlined in example 12, N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (500 mg, 2 mmol) and 2-trifluoromethylphenylisothiocyanate (548 mg, 2 mmol) were coupled to form the desired thiourea (469 mg, 52%). EI-MS m/z 454.0 (M+).
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[O:7])(C)(C)C.Cl.[C:32]([O:36][C:37]([NH:39][C@H:40](C(O)=O)[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCOCC1>[C:32]([O:36][C:37]([NH:39][C@H:40]([C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH:20]([CH3:21])[CH3:22])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])=[O:7])[CH2:41][C:42]1[N:43]=[CH:44][S:45][CH:46]=1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A mixture of 370 mg (0.87 mmole) of (2S, 4S, 5S)-5-(t-butoxycarbonyl)amino-6-cyclohexyl-4-hydroxy-2-isopropyl-N-butylhexanamide (prepared as described in Preparation 4) and 5 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with diethyl ether. The solvent was once again removed by distillation under reduced pressure. This operation was repeated three times, and the final residue was then dried in vacuo for 8 hours. At the end of this time, the dried material was suspended in 10 ml of anhydrous tetrahydrofuran, and 260 mg (0.96 mmole) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to the suspension. After this, 0.15 ml (0.99 mmole) of 95% diethyl cyanophosphonate and 0.27 ml (1.94 mmole) of triethylamine were added, in that order, to the suspension, whilst ice-cooling and under an atmosphere of nitrogen, after which the mixture was stirred for 6 hours. The reaction mixture was then freed from the solvent by evaporation under reduced pressure, and the resulting residue was purified by medium pressure column chromatography through silica gel (using a 20:1 by volume mixture of methylene chloride and methanol as the eluent) to afford 470 mg (yield 93%) of the title compound as white crystals, melting at 201°-203° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[C:11]([N:22](S(C2C=CC(C(C)C)=CN=2)(=O)=O)[S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][N:27]=2)(=[O:25])=[O:24])[N:10]([CH3:47])[N:9]=1)(=O)C.[OH-].[Na+]>C(O)C>[O:17]1[C:16]2[CH:20]=[CH:21][C:13]([C:12]3[C:8]([O:7][CH2:6][CH2:5][OH:4])=[N:9][N:10]([CH3:47])[C:11]=3[NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][N:27]=3)(=[O:25])=[O:24])=[CH:14][C:15]=2[O:19][CH2:18]1
Reactant: CC(=O)OCCOc1nn(C)c(N(S(=O)(=O)c2ccc(C(C)C)cn2)S(=O)(=O)c2ccc(C(C)C)cn2)c1-c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2C)nc1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of 2-[(4-(1,3-benzodioxol-5-yl)-5{-bis[(5-isopropyl-2-pyridinyl)sulfonyl]amino}-1-methyl-1H-pyrazol-3-yl)oxy]ethyl acetate (Preparation 14) (9.0 g) in ethanol (200 ml) was added 2.0M aqueous sodium hydroxide (25 ml). The reaction was stirred for 30 min and concentrated under reduced pressure and the residue was poured onto 0.5M aqueous citric acid (300 ml). This was extracted with ethyl acetate (3×80 ml) and dried over magnesium sulfate. The solvent was removed under reduced pressure and the crude residue was purified by silica (230 g) chromatography eluting with a gradient of 50% ethyl acetate in hexane to 70% ethyl acetate in hexane to afford the title product as a white solid (5.0 g)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>CN1CCCC1=O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNS(C)(=O)=O
Reaction time: 18 h
Yield: 12.2 %

Procedure:
A solution of the compound of Example 51, 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.570 g, 5.50 mmol) in 40 mL of 1-methyl-2-pyrrolidinone was treated with triethylamine (1.53 mL, 11.0 mmol). With vigorous stirring, methanesulfonyl chloride (0.426 mL, 5.50 mmol) was added dropwise. After 18 h, the reaction was treated with 50 mL of water and then concentrated to yield a solid. The solid was purified by column chromatography (SiO2, 90:10:0.5 CHCl3:MeOH:NH4OH) to yield 244 mg of N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}methanesulfonamide as a white solid.
Reaction SMILES: C(OC([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[C:14]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C@H:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH3:33])[CH:26]=3)=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[NH:16][CH:17]=2)[CH2:9][CH2:8]1)=O)C=C.O1CCOCC1.N1CCCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[NH:16][CH:17]=[C:13]([C:10]3[CH2:11][CH2:12][NH:7][CH2:8][CH:9]=3)[C:14]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C@H:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:33])[CH:26]=2)=[CH:23][CH:22]=1
Reactant: C=CCOC(=O)N1CC=C(c2c[nH]c(-c3ccc(F)cc3)c2-c2ccnc(N[C@@H](C)c3ccccc3)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCNC1
Product: C[C@H](Nc1cc(-c2c(C3=CCNCC3)c[nH]c2-c2ccc(F)cc2)ccn1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.2 %

Procedure:
A mixture of 229 mg (0.44 mmol) of 4-(1-allyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-[2-(1(S)-phenylethylamino)pyridin-4-yl]-1H-pyrrole [prepared as described in step 73(iii) above] in 2.5 ml of a 10:1 by volume mixture of dioxane and water, 55 μl (0.66 mmol) of pyrrolidine and 5 mg (0.0044 mmol) of tetrakis(triphenylphosphine)palladium (0) was stirred at 0° C. for 10 minutes. At the end of this time, water was added to the reaction mixture and then this was extracted with ethyl acetate. The organic extract was washed with water and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 10:1:1 by volume mixture of ethyl acetate, methanol and isopropylamine as the eluant to give 41 mg (yield 21%) of the title compound as a pale brown amorphous solid.
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:22]([OH:23])[C@@H:21]([CH2:24][O:25][C@H:26]3[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@@H:27]3[OH:28])[O:20][C@H:15]([O:16][CH2:17][CH2:18][NH2:19])[C@H:14]2[OH:37])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[CH2:38]([O:45][C:46](=[O:64])[C@@H:47]([NH:53][C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[CH2:48][CH2:49][C:50](O)=[O:51])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:57]([O:56][C:54]([NH:53][C@@H:47]([CH2:48][CH2:49][C:50]([NH:19][CH2:18][CH2:17][O:16][C@H:15]1[O:20][C@H:21]([CH2:24][O:25][C@H:26]2[O:34][C@H:33]([CH2:35][OH:36])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@@H:27]2[OH:28])[C@@H:22]([OH:23])[C@H:13]([O:12][C@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]2[OH:3])[C@@H:14]1[OH:37])=[O:51])[C:46]([O:45][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:64])=[O:55])[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-aminoethyl α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranoside (2.6 g, 4.75 mmol), and (S)-5-(benzyloxy)-4-{[(benzyloxy)carbonyl]amino}-5-oxopentanoic acid (2.0 g, 5.39 mmol) in DMF (36 mL) at 0° C. was added DMAP (580 mg, 4.75 mmol) and EDC (3.64 g, 19.00 mmol). The reaction mixture was allowed to gradually warm up to rt. After stirring for 16 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel (275 g), eluting with 10-55% AcCN in H2O to give the title compound. UPLC Method B: calculated for C40H56N2O21 900.34, observed m/e: 901.26 [M+1]; Rt=2.46 min.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[N:4]1)[CH3:2].Cl[C:18]1[N:23]=[N:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([N:30]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([F:39])[CH:37]=4)[CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:18]2[N:23]=[N:22][C:21]([N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([F:39])[CH:37]=5)[CH2:32][CH2:31]4)[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Product: CCn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, reacting 1-ethylpyrazole-4-boronic acid pinacol ester and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[C:6]([OH:13])[CH:5]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([OH:13])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(C)=O)c(O)c1
Agent: [Pd]
Solvent: CO
Product: CCOc1ccc(CC)c(O)c1
Reaction time: 24 h
Yield: 97 %

Procedure:
1-(4-Ethoxy-2-hydroxy-phenyl)-ethanone was dissolved in MeOH (40 mL), treated with 10 wt % Pd/C (1.4 g, Degussa type) and stirred under a balloon of H2 for 24 hours. The reaction mixture was filtered through a pad of celite washing with EtOAc. The filtrate was concentrated to give the product as an oil (3.12 g, 97%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.6 Hz, 3 H), 1.39 (t, J=7.1 Hz, 3 H), 2.56 (d, J=7.6 Hz, 2 H), 3.98 (d, J=7.1 Hz, 2 H), 4.79 (s, 1 H), 6.37 (d, J=2.5 Hz, 1 H), 6.44 (dd, J=8.3, 2.5 Hz, 1 H), 7.01 (d, J=8.3 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:31]([CH2:30][Cl:29])(=[O:33])=[O:32])[CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Reactant: O=S(=O)(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)CCl)CC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (2.5 g) and triethylamine (1.7 g) in dichloromethane (35 ml) was added at 0° C. a solution of chloromethanesulfonyl chloride (1.26 g) in dichloromethane (2 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with water, 10% citric acid solution and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless syrup of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(chloromethanesulfonyl)-2-piperazinone (2.47 g).