Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][CH:28]([C:32]([OH:34])=O)[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:35]([N:38](CC)C(C)C)(C)C.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][C@@H:28]([C:32]([NH:38][CH3:35])=[O:34])[CH2:27]3)(=[O:24])=[O:25])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCOC(C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)[C@H]1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)CCO1
Yield: 78 %

Procedure:
Following the same procedure in Example 112, Step A, using 4-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)morpholine-2-carboxylic acid (500 mg, 1 mmol), N,N-diisopropylethylamine (1 mL, 5 mmol), methylamine (0.75 mL, 2.0M in THF, 1.5 mmol) and HATU (456 mg, 1.2 mmol) in DMF (10 mL). The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 400 mg (78% yield) as white solid racemic mixture of the title compound. The two enantiomers were separated on a chiral OD 5 microns column using 20% ethanol:hexane. [α]D: +37.4 (c=1.00, MeOH). 1H NMR (400 MHz, METHANOL-D4) δ 1.37-1.46 (m, 2 H), 1.48 (s, 9 H), 1.53-1.73 (m, 4 H), 1.88-2.01 (m, 2 H), 2.04-2.18 (m, 2 H), 2.29 (m, 1 H), 2.59 (s, 3 H), 3.43-3.49 (m, 1 H), 3.59 (m, 1 H), 3.77-3.85 (m, 1 H), 3.87-3.96 (m, 2 H), 4.30 (d, J=7.62 Hz, 2 H), 7.54 (dd, J=8.69, 1.66 Hz, 1 H), 7.67 (d, J=8.59 Hz, 1 H), 7.93 (d, J=1.76 Hz, 1 H); MS (APPI) (M+H)+=513.3; Anal. Calc. for C24H34F2N4O4S+1.5 TFA: C, 47.44; H, 5.23; N, 8.20. Found: C, 47.54; H, 4.91; N, 8.00.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH:9]=2)[NH:4][N:3]=1>C(#N)C>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:3]=[C:2]3[I:1])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3[nH]nc(I)c3c2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)c(I)nn3C(=O)OC(C)(C)C)CC1
Yield: 148.7 %

Procedure:
A solution of tert-butyl 4-(3-iodo-1H-indazol-5-yl)piperidine-1-carboxylate (218. mg; 0.51 mmol; 1.0 eq.), di-tert-butyldicarboxylate (145 mg; 0.66 mmol; 1.3 eq.), diméthylamino-4-pyridine (12.5 mg; 0.10 mmol; 0.20 eq.) and TEA (86.0 μl; 0.61 mmol; 1.2 eq.) in acetonitrile (6.5 mL) was stirred at RT O/N. Acetonitrile was removed under reduced pressure, the residue was diluted with water and extracted three times with Ether. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (heptane/EtOAc, gradient from 90:10 to 75:25) to give the title compound as a colorless oil (200 mg, 74%). 1H NMR (300 MHz, DMSO-d6) δ 7.99 (d, J=8.7 Hz, 1H), 7.62 (dd, J=1.6, 8.7 Hz, 1H), 7.35 (s, 1H), 4.18-4.03 (m, 2H), 2.96-2.73 (m, 3H), 1.87-1.75 (m, 2H), 1.64 (s, 9H). 1.61-1.48 (m, 2H), 1.42 (s, 9H). (Condition A): Rt 6.33 min (purity 99.8%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)[CH2:26][CH2:25]2)[CH:19]=1)=[O:16]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccnc2ccccc12
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccnc4ccccc34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-quinolinecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 388.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH3:13])=O)=[CH:4][CH:3]=1>O1CCCC1.CO.Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:11][CH2:12][CH3:13])=[CH:6][CH:7]=1
Reactant: CCNC(=O)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCNCCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-N-ethyl-acetamide (preparation 80), (437 mg, 2.22 mmol) and borane tetrahydrofuran complex (1M, 8.88 mL, 8.88 mmol) in tetrahydrofuran was heated under reflux for 18 hours. The cooled reaction mixture was then diluted with methanol (5 mL) and 12M hydrochloric acid (2 mL) and the re-heated to reflux for a further hour. The mixture was cooled to room temperature and concentrated in vacuo. Trituration of the residue with ethyl acetate afforded the title compound as a colourless solid in 99% yield, 403 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl[C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>N1C=CC=CC=1>[CH3:28][O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])=[CH:17][CH:18]=1)=[O:29]
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: COC(=O)CCCCC(=O)Nc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (1.0 g, 3.98 mmol) in anhydrous pyridine (20 mL) was added dropwise methyl 6-chloro-6-oxohexanoate (Fluka) (750 μL) at rt. After 30 min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 970 mg) was added and the resulting mixture was stirred overnight at rt. After filtration and rinsing the resin, water (160 mL) was added into the filtrate and a white solid precipitated out. Filtration and washing with water gave a white solid, which was dried under vacuo at 50° C. for 5 hrs. The title compound (981 mg) was obtained as a white solid (63%) in 99.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[N:1]1([CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCn1ccc2cccnc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1SC(Cc2ccc(OCCn3ccc4cccnc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 79.5 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.77 g of 2-(7-azaindol-1-yl)ethanol (prepared as described in Preparation 18), 4.40 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 2.35 ml of tributylphosphine, 2.39 g of 1,1'-(azodicarbonyl)dipiperidine and 45 ml of anhydrous benzene were used, to give 4.58 g of the title compound, melting at 167.5-168.9° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[NH:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([C:2]([F:24])([F:1])[F:23])=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12
Reactant: CN(C)CCCN
Product: CN(C)CCCNC(=O)c1ccccc1Nc1ccnc2cc(C(F)(F)F)ccc12

Procedure:
2-(7-Trifluoromethyl-4-quinolylamino)benzoic acid is converted to the acid chloride which is reached with 3-dimethylaminopropylamine as in Example 1 to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([NH:43][CH2:44][CH3:45])=O>>[CH2:41]([NH:43][CH2:44][CH2:45][O:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:4][CH:3]=1)[CH3:40]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: CCNC(=O)CCl
Product: CCNCCOc1ccc(CN(c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)C(C)C)cc1
Yield: 7.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (31 mg) and 2-chloro-N-ethylacetamide (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.2 mg) was obtained.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C@H:11]([OH:15])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20]O>>[O:1]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C@H:11]([OH:15])[C:12]([O:14][CH3:20])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: Cl
Product: COC(=O)[C@@H](O)c1cccc(Oc2ccccc2)c1
Reaction time: 24 h

Procedure:
(S)-3-Phenoxymandelic acid (13.0 g) was added to a solution of dry hydrogen chloride (15.0 g) in methanol (100 ml) and the solution thus obtained kept at the ambient temperature for 24 hours after which period the volatile portion was evaporated yielding methyl (S)-3-phenoxymandelate as a residual oil. This was then added to liquid ammonia (20 ml) in a pressure vessel which was then sealed and temperature of the mixture allowed to rise to the ambient temperature over a period of 24 hours. The vessel was then opened and the excess of ammonia allowed to evaporate. The residual material was stirred with water and the solid collected by filtration, and recrystallised from benzene (70 ml) to yield impure (S)-3-phenoxymandelamide, m.p. 93° C. [α]D25 + 25.4° (C, 2.0, methanol), (approximately 80% optically pure).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:13]([CH3:16])([O-:15])=[O:14]>>[CH3:12][O:11][C:1](=[O:10])[CH2:2][CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: COC(=O)C=Cc1ccccc1
Reactant: C[N+](=O)[O-]
Product: COC(=O)CC(C[N+](=O)[O-])c1ccccc1
Yield: 59 %

Procedure:
A solution of methyl cinnamate (4.93 g, 30.4 mmol) and teteramethylguanidine (3.99 g, 34.6 mmol) in nitromethane (30 ml) was stirred for 6 hours at 90° C. After removal of the solvent under reduced pressure, the residue was partitioned between water and ethyl acetate, and the organic layer was washed with water and brine and then dried over sodium sulfate. The organic solvents were removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=4/1) to afford 4-nitro-3-phenyl-butyric acid methyl ester (4.02 g, 59%)
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[C:22]([O-:25])(=[S:24])[CH3:23].[K+]>C(#N)C.C(OC(=O)C)C>[C:22](=[O:25])([S:24][CH2:2][C:3](=[O:4])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)[CH3:23]
Reactant: CC([O-])=S
Reactant: O=C(CBr)Nc1cccc(-c2cnc3ccccc3n2)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)SCC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 140 °C
Yield: 13.5 %

Procedure:
A mixture of 2-bromo-N-(3-(quinoxalin-2-yl)phenyl)acetamide (300 mg, 0.876 mmol) and potassium thioacetate (400 mg, 3.5 mmol) in acetonitrile (15 mL) was heated in microwave at 140° C. for 10 min. The dark red solution was diluted with ethylacetate (50 mL), washed with brine (2×50 mL), dried over sodium sulphate, the solvent was evaporated in vacuo and the residue was purified by flash column chromatography (Flash Master, 20 g Isolute Silica column, gradient 0 to 5 min hexane, then ethyl acetate up to 50% over 20 min) to afford S-2-oxo-2-(3-(quinoxalin-2-yl)phenylamino)ethyl ethanethioate (40 mg, 13% yield). LCMS calculated for C18H15N3O2S (M+H): 338.40. found 338. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.45 (1H, br.), 9.50 (1H, s), 8.51 (1H, m), 8.11-8.18 (2H, m), 8.05-8.08 (1H, m), 7.80-7.95 (3H, m), 7.55-7.60 (1H, m), 3.90 (2H, s), 2.41 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])[C:4]([C:12]#[N:13])=[C:5]([C:10]#[N:11])[C:6](=[O:9])[C:7]=1[Cl:8].C1(C)C=CC=CC=1>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[C:5]([C:10]#[N:11])=[C:4]([C:12]#[N:13])[C:3]=1[OH:14]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: N#Cc1c(O)c(Cl)c(Cl)c(O)c1C#N

Procedure:
The ⟦2,3-dihydroxanthotoxin⟧ 4',5'-dihydroxanthotoxin thus obtained is then dehydrogenated. This advantageously is effected by heating the ⟦2,3-dihydroxanthotoxin⟧ 4',5'-dihydroxanthotoxin with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a substantially inert solvent, for example, toluene or chlorobenzene, advantageously at reflux, until substantial dehydrogenation is obtained. The 2,3-dichloro-5,6-dicyano-hydroquinone formed and any residual 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are removed and the product taken up in chloroform and recovered therefrom. If substantial amounts of the residual 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are present, it is desirable to convert this to the corresponding hydroquinone with sodium dithionite, dissolve the hydroquinone in aqueous sodium bicarbonate, and extract the sodium bicarbonate solution with chloroform to recover the 8-methoxypsoralen which can be recovered by drying over sodium sulphate and concentrating to dryness. The resulting product can then be recrystallized from benzene or any suitable inert solvent in which 8-methoxypsoralen has limited solubility. If there is little residual 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, the reaction mixture can be cooled and the precipitated hydroquinone filtered off and the reaction mixture, i.e., the filtrate, then extracted with chloroform. If desired, the filter cake can be extracted with benzene or like solvents such as chlorobenzene, toluene, and the like, for example, by refluxing the filter cake in the solvent and then adding the extract to the reaction mixture filtrate prior to the chloroform extraction. The chloroform solution is then washed successively with dilute sodium bisulfite solution, dilute sodiium bicarbonate solution, and water and dried over sodium sulfate. The resulting chloroform solution is then concentrated by distillation until the product precipitates and an inert non-solvent such as hexane or like aliphatic or cycloaliphatic hydrocarbon is added to cause further precipitation of the product and the product is filtered. If desired, the product can be further purified by redissolving it in chloroform, or chloroform containing a minor amount of ethyl acetate, passing the solution over an alumina column concentrating the effluent until crystallization takes place, adding hexane or like solvent further to cause precipitation of the product, and filtering the solution.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=3)=[O:12])=[CH:9][N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][C:33]#[CH:34])([CH3:28])([CH3:27])[CH3:26].C(NC(C)C)(C)C>C1COCC1.[Cu](I)I.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>[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][C:33]#[C:34][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:9]=2)=[O:12])[CH:14]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: O=C(c1cccc(I)c1)c1cn(C2CCCC2)c2ncnc(Cl)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC#Cc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(Cl)c23)c1
Yield: 85.8 %

Procedure:
A solution of (4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-iodo-phenyl)-methanone (500 mg, 1.1 mmol), Prop-2-ynyl-carbamic acid tert-butyl ester (341 mg, 2.2 mmol), Copper Iodide (21 mg, 0.11 mmol), PdCl2(PPh3)2 (77 mg, 0.11 mmol), and diisopropylamine (111 mg, 1.1 mmol) in THF (25 mL) was stirred at room temperature under N2. After 24 h the reaction was quenched with saturated aqueous NH4Cl and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated. Purification by flash column chromatography (hexanes/ethyl acetate 7:3) afforded the title compound as a yellow solid (452 mg, 86%). %). MS: 479.2/481.2 (MH+); HPLC Rf: 7.26 min. (HPLC method 4).
Reaction SMILES: Cl.[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][CH2:18][C:17]3([O:24][CH:23]([C:25]4[O:26][C:27]([CH3:30])=[CH:28][N:29]=4)[CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:15]2)=[O:13])=[CH:8][C:7]=1[CH3:31])([CH3:4])[CH3:3].FC(F)(F)S(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O.C([O-])(O)=O.[Na+]>CCO>[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:19][CH2:18][C:17]3([O:24][CH:23]([C:25]4[O:26][C:27]([CH3:30])=[CH:28][N:29]=4)[CH2:22][N:21]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:20]3)[CH2:16][CH2:15]2)=[O:13])=[CH:8][C:7]=1[CH3:31])([CH3:4])[CH3:3]
Reactant: Cc1cnc(C2CNCC3(CCN(C(=O)c4ccc(OC(C)C)c(C)c4)CC3)O2)o1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cnc(C2CN(CC(F)(F)F)CC3(CCN(C(=O)c4ccc(OC(C)C)c(C)c4)CC3)O2)o1
Temperature: 80 °C
Yield: 8.6 %

Procedure:
A mixture of (4-isopropoxy-3-methyl-phenyl)-[10-(5-methyloxazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone hydrochloride salt (32 mg, 0.07 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (17 μL, 0.11 mmol) and NaHCO3 (24 mg, 0.28 mmol) in anhydrous EtOH (800 μL) was heated at 80° C. in a sealed vial for 18 hours. The reaction mixture was allowed to cool to room temperature, microfiltered and purified by Waters mass directed LC/MS: (10-99% ACN/H2O (5 mM HCl)) and concentrated in vacuo to yield (4-isopropoxy-3-methyl-phenyl)-[10-(5-methyloxazol-2-yl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone (3 mg, 9%) as a white solid. ESI-MS m/z calc. 495.5. found 496.7 (M+1)+; Retention time: 1.99 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.27-7.13 (m, 2H), 6.96 (d, J=9.0 Hz, 1H), 6.82 (d, J=1.2 Hz, 1H), 4.86 (dd, J=12.0, 4.7 Hz, 1H), 4.71-4.54 (m, 1H), 3.32-3.14 (m, 5H), 3.07 (dd, J=11.5, 2.6 Hz, 1H), 2.90-2.83 (m, 1H), 2.70 (dd, J=18.3, 7.2 Hz, 1H), 2.41-2.23 (m, 6H), 2.13 (s, 3H), 1.64-1.39 (m, 3H), 1.29 (d, J=6.0 Hz, 6H).
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O)[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(Cl)(Cl)Cl>C(O)C>[CH2:1]([N:7]([CH2:21][CH2:22][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[S:8]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)(=[O:9])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1CCNCC1
Reactant: CCCCCCN(CCOS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1cccc2cnccc12
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCCCN(CCN1CCCCC1)S(=O)(=O)c1cccc2cnccc12
Temperature: 80 °C
Yield: 80 %

Procedure:
In 30 ml of ethanol were dissolved 5.47 g of N-hexyl-N-(2-p-toluenesulfonyloxyethyl)-5-isoquinolinesulfonamide and 2.85 g of piperidine, and the solution was heated in a pressure vessel at 80° C. for 3 hours. To the mixture obtained was added 100 ml of chloroform, and the resultant mixture was washed with 100 ml of water and dried with anhydrous magnesium sulfate. The chloroform was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, solvent: 3% methanol solution in chloroform) to obtain 3.6 g of N-hexyl-N-(2-piperidinoethyl)-5-isoquinolinesulfonamide [Compound (45)]. Compound (45) was analyzed to give the following data.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[OH:15])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>C(OCC)(=O)C>[NH2:26]/[C:4](/[C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[Cl:1])=[C:6]1\[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[S:10]\1
Reactant: N
Reactant: O=C(c1ccccc1Cl)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1Cl
Yield: 33 %

Procedure:
Prepared as in Example 1 from 2-(2-chlorobenzoyl)-benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia with a yield of 33% of theory; m.p. 167°-168° C. (ethyl acetate)
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N:18]2[CH2:23][CH2:22][C@@H:21]([NH2:24])[C@H:20]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:19]2)[C:16]=1[Cl:17])[C:12]#[N:13]>ClCCl>[NH2:8][C:9]1[C:16]([Cl:17])=[C:15]([N:18]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:5](=[O:7])[CH3:6])[C@H:20]([O:25][Si:26]([C:29]([CH3:31])([CH3:30])[CH3:32])([CH3:27])[CH3:28])[CH2:19]2)[CH:14]=[C:11]([C:12]#[N:13])[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CN(c2cc(C#N)cc(N)c2Cl)CC[C@H]1N
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
Acetic anhydride (0.011 mL, 0.119 mmol) was added to a solution of (+/−)-3-amino-5-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-4-chlorobenzonitrile (Example 171D), (41 mg, 0.108 mmol) in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 0.5-5% methanol/dichloromethane). (+/−)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)acetamide (44 mg) was obtained as a colorless oil which solidified upon standing.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:29]O.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:32][CH2:29][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=1[F:20]
Reactant: BrC(Br)(Br)Br
Reactant: COc1cccc(CO)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(CBr)c1F

Procedure:
Triphenylphosphine (11.1 g) was added to a solution of the subtitle product of step ii) (5.0 g) in DCM (200 ml) followed by the portionwise addition of carbon tetrabromide (14.0 g). The reaction was stirred for 4 h before the addition of further triphenylphosphine (2.0 g) and carbon tetrabromide (2.0 g) and stirring maintained for 1 h. The mixture was concentrated to 30 ml volume and diluted in Et2O (300 ml). The solid precipitate was filtered and washed with Et2O (3×) and the filtrate concentrated in vacuo. The residue was purified by column chromatography (10% Et2O/iso-hexane) to afford the subtitle compound as a clear oil. Yield: 5.2 g.