Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-][Mn](=O)(=O)=O.[K+].[CH2:16]1COCC1>>[NH2:1][C:2]1[C:7]([CH:8]([OH:9])[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1C=O
Reactant: C1CCOC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CC(O)c1cccnc1N
Temperature: 25 °C

Procedure:
To a dry flask (dried with a heat gun under argon purge) was added dry THF (400 mL) and MeLi—LiBr (137 mL of a 1.5M solution in Et2O, 204.9 mmol) via cannula. This solution was cooled to −78° C. when a solution of 2-aminopyridine-3-carboxaldehyde (10.0 g, 82.0 mmol) in THF (150 mL) was added dropwise via a pressure equalizing addition funnel over ˜45 with vigorous stirring (exotherm observed, orange color persisted). Upon complete addition, the solution was allowed to stir for 1 hour at −78° C., at which time TLC (KMnO4 stain with heat) indicated that most of the starting material had been converted to product. The reaction was quenched very carefully with water (200 mL; dropwise initially), diluted with EtOAc (200 mL) and allowed to warm to rt. The layers were separated and the aqueous layer was extracted with 3% MeOH in EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Analogix; 0 to 5% MeOH in EtOAc) to give 7.78 g (68%) of the desired racemic product as a yellow oil that solidified under high vac over several days. This material was separated into its respective enantiomers (>98% ee) by SFC with a chiralcel OD-H (20×250 mm) column (10% EtOH/0.1% isopropylamine in heptane/0.1% isopropylamine).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[C:14]([NH2:16])=[O:15])[CH:5]=[C:4](Cl)[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29])#[N:19]>O1CCOCC1.C([O-])(O)=O.[Na+].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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[C:14]([NH2:16])=[O:15])[CH:5]=[C:4]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([F:29])[CH:22]=2)[N:3]=1
Reactant: NC(=O)C1COCCN1c1cc(Cl)nc(N)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCOCC3C(N)=O)nc(N)n2)cc1F
Temperature: 95 °C
Reaction time: 18 h
Yield: 69.6 %

Procedure:
A mixture of 4-(2-amino-6-chloro-4-pyrimidinyl)-3-morpholinecarboxamide (390 mg, 1.51 mmol), Pd(PPh3)4 (91 mg, 0.08 mmol), and (4-cyano-3-fluorophenyl)boronic acid (285 mg, 1.73 mmol) in 1,4-dioxane (6 mL) and saturated aqueous NaHCO3 (2 mL) was stirred at 95° C. under argon in a sealed tube for 18 hours. The mixture was cooled, quenched with saturated aqueous NaHCO3 (25 mL) and extracted with EtOAc (3×25 mL). The extracts were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (34 g, SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (360 mg) as a white solid. LC-MS (ES) m/z=343 [M+H]+.
Reaction SMILES: C(OC(=O)[C:7]([C:36]#[N:37])=[C:8]([NH:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:20])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:27]=[C:22]([NH:21][C:8]([NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:20])=[CH:7][C:36]#[N:37])[CH:23]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:25]=1
Reactant: CC(C)(C)OC(=O)C(C#N)=C(NCCCN1CCCCCC1=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC=C(NCCCN1CCCCCC1=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 114.5 %

Procedure:
To a solution of 3-[3,5-bis(trifluoromethyl)phenylamino]-2-cyano-3-[3-(2-oxoazepan-1-yl)propylamino]acrylic acid tert-butyl ester (203 mg, 0.37 mmol) in DCM (6.0 mL) at 0° C. TFA (6.0 mL) was added. The resulting mixture was stirred at 0° C. for 30 min and then poured into an ice-cold, aqueous, saturated NaHCO3 -solution (100 mL). After dilution with DCM (30 mL) phases were separated, the aqueous layer was extracted (3×20 mL DCM), the combined extracts were washed with brine (2×50 mL), dried (magnesium sulfate) and concentrated, to yield 190 mg (100%) of the title compound as an oil (mixture of isomers). LCMS: elution at 9.97 min, MH+ : 449). 1H NMR (300 MHz, DMSO-d6): δ=1.45-1.80 (m, 8H), 2.40 (m, 2H), 2.95 (m, 1H), 3.21 (m, 2H), 3.35 (m, 6H), 3.58 (s, br, 1H), 7.35-7.70 (m, 3H).
Reaction SMILES: [C:1]([N:5]1[CH:13]=[C:12]2[C:7]([C:8](=[O:41])[NH:9][C:10]3([CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][N:27]=[C:28]5[NH:31]CC5C=CC(OC)=CC=5)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)[CH2:11]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:31][C:28]1[C:29]2[C:24](=[CH:23][CH:22]=[C:21]([C:19]([N:16]3[CH2:17][CH2:18][C:10]4([NH:9][C:8](=[O:41])[C:7]5=[N:6][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]=[C:12]5[CH2:11]4)[CH2:14][CH2:15]3)=[O:20])[CH:30]=2)[CH:25]=[CH:26][N:27]=1
Reactant: COc1ccc(CNc2nccc3ccc(C(=O)N4CCC5(CC4)Cc4cn(C(C)(C)C)nc4C(=O)N5)cc23)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)c3ccc4ccnc(N)c4c3)CC1)C2
Temperature: 65 °C
Reaction time: 19 h
Yield: 32.2 %

Procedure:
To a solution of 2′-tert-butyl-1-(1-(4-methoxybenzylamino)isoquinoline-7-carbonyl)-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one (28 mg, 0.051 mmol) in trifluoroacetic acid (0.51 mL) was added anisol (8.3 μL, 0.076 mmol). The reaction was heated to 65° C. and stirred for 19 hours. The reaction was concentrated. Purification by reversed-phase HPLC gave the title compound (7.1 mg, 32%). +ESI (M+H) 433.2; HPLC retention time 1.79 minutes (Method A).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[NH2:13][C:14]([CH:18]([F:20])[F:19])=[CH:15][C:16]#[N:17]>C(O)(=O)C.CO.ClCCl>[F:19][CH:18]([F:20])[C:14]1[NH:13][C:14]([CH:18]([F:20])[F:19])=[C:15]([C:16]#[N:17])[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:15]=1[C:16]#[N:17]
Reactant: N#CC=C(N)C(F)F
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12

Procedure:
A solution of 80 mg (0.50 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A) and 130 mg (1.10 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in acetic acid (0.5 ml) containing powdered 4 Å molecular sieve was heated to reflux temperature for 3.5 h. After cooling, the reaction mixture was diluted with methanol/dichloromethane and filtered. The filtrate was evaporated, and the residue was purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) yielding 61 mg (34% of th.) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:15][CH3:16])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C=CC=1)C(OO)=[O:22]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:15][CH3:16])[CH2:13][CH2:12][N+:11]([O-:22])([CH3:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC1(c2ccc(F)c(F)c2)CCN(C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC1(c2ccc(F)c(F)c2)CC[N+](C)([O-])C1

Procedure:
Preparation according to Example 32: Enantiomer 2 of 3-(3,4-difluorophenyl)-3-methoxy-1-methylpyrrolidine (0.012 g, 0.052 mmol), dichloromethane (2 ml), 3-chloroperoxybenzoic acid (77%) (0.023 g, 0.104 mmol). The crude product was analyzed by LCMS (Qtrap, Applied Biosystems, Q1 MS), analysis showed <95% conversion: MS (m+1)/z; 244 (M+1, bp), 243 (4), 214 (9), 150 (3).
Reaction SMILES: [CH:1]([N:4]([CH:6]([CH3:8])[CH3:7])O)([CH3:3])[CH3:2].[H-].[Na+].[N+:11]([C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[C:24]([CH2:27]Cl)=[N:25][N:26]=[C:22]3[CH2:21][N:20]=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:18]=2[CH:36]=1)([O-:13])=[O:12]>CN(C)C=O>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[C:24]([CH2:27][N:4]([CH:6]([CH3:8])[CH3:7])[CH:1]([CH3:3])[CH3:2])=[N:25][N:26]=[C:22]3[CH2:21][N:20]=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:18]=2[CH:36]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: CC(C)N(O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2)C(C)C

Procedure:
In the manner given in Example 16, a solution of N,N-diisopropylhydroxylamine in dimethylformamide is treated with sodium hydride suspended in mineral oil, and the mixture is treated with 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine to give 8-nitro-1-[(diisopropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: [H-].[K+].[Cl:3][C:4]1[C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:8]=2[C:7]([OH:16])=[CH:6][CH:5]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[Cl:3][C:4]1[C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:8]=2[C:7]([O:16][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: CN1CCc2c(O)ccc(Cl)c2CC1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cl)c2c1CCN(C)CC2
Reaction time: 0.33 h
Yield: 76 %

Procedure:
A 35% dispersion of potassium hydride in mineral oil (2.6 g, 23 mmol) in dimethylformamide (40 ml) was stirred and treated with 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-ol (4.0 g, 19 mmol), stirred for 20 minutes, treated with ethyl bromoacetate (3.8 g, 23 mmol) and stirred for 72 hours. The mixture was concentrated, partitioned between water and methylene chloride and the organic phase was washed, dried with magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluted with methanol-methylene chloride (8:92) to give 4.3 g of ethyl [(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)oxy]acetate.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N:32]1[C:40]2[C:35](=[N:36][CH:37]=[CH:38][CH:39]=2)[N:34]([C:41]2[CH:42]=[C:43]3[C:47](=[CH:48][CH:49]=2)[CH:46]([C:50](O)=[O:51])[CH2:45][C:44]3=[O:53])[CH:33]=1.[C:54]([C:58]1[CH:59]=[C:60]([NH2:69])[N:61]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[N:62]=1)([CH3:57])([CH3:56])[CH3:55]>CN(C=O)C>[C:54]([C:58]1[CH:59]=[C:60]([NH:69][C:50]([CH:46]2[C:47]3[C:43](=[CH:42][C:41]([N:34]4[C:35]5=[N:36][CH:37]=[CH:38][CH:39]=[C:40]5[N:32]=[CH:33]4)=[CH:49][CH:48]=3)[C:44](=[O:53])[CH2:45]2)=[O:51])[N:61]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[N:62]=1)([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C1CC(C(=O)O)c2ccc(-n3cnc4cccnc43)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)C2CC(=O)c3cc(-n4cnc5cccnc54)ccc32)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
HATU (46.7 mg, 0.12 mmol) and triethylamine (29.5 μL, 0.21 mmol) are added to a solution of (R/S)-5-imidazo[4,5-b]pyridine-3-yl-3-oxo-indan-1-carboxylic acid (30 mg, 0.1 mmol) in DMF (2.5 mL). The reaction is stirred at rt for 2 min then 5-tert-butyl-2-phenyl-2H-pyrazol-3-ylamine (21.5 mg, 0.1 mmol) is added. After stirring at rt for 8 h, DMF is removed in vacuo. The residue is purified by reversed phase MPLC using ACN/Water as eluant and 5-imidazo[4,5-b]pyridine-3-yl-3-oxo-indan-1-carboxylic acid (5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-amide is obtained as a white solid. Title compound: ES-MS: 491.00 [M+H]+, tR=1.6 min (System 2).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH:25](=O)[CH3:26]>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:25][CH3:26])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CC=O
Agent: Cl
Product: CCN1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively aminated with acetaldehyde in analogy to experiment L3 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-ethyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 382.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)[C:10](=[O:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)=[O:60])([CH3:57])([CH3:56])[CH3:55]>CC(N(C)C)=O>[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][N:64]([C:19]([C@H:16]2[CH2:15][CH2:14][C@H:13]([CH2:12][N:11]3[C:10](=[O:22])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]3=[O:1])[CH2:18][CH2:17]2)=[O:20])[CH2:63][CH2:62]1)=[O:60])([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=c1[nH]c2ccccc2c(=O)n1C[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)[C@H]2CC[C@H](Cn3c(=O)[nH]c4ccccc4c3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-4-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-cyclohexanecarboxylic acid (1.5 g, 4.96 mmol) in dimethylacetamide (10 mL), HATU (1.88 g, 4.96 mmol) and triethylamine (0.76 mL, 5.45 mmol) were added and the mixture left stirring at room temperature for 1 hour. Then tert-butyl-1-piperazinecarboxylate (0.92 g, 4.96 mmol) was added and the reaction left stirring for 18 h at room temperature. The solvent was removed under reduced pressure and the residue was washed with a 0.4M Na2CO3 solution. The titled compound was obtained as a white solid (2.3 g, quantitative yield).
Reaction SMILES: C([CH:8]([NH2:32])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:29])[CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:13][C:12]=1[O:30][CH3:31])(OC(C)(C)C)=O.[ClH:33].C(OCC)C>O1CCOCC1>[ClH:33].[NH2:32][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:29])[CH2:20][C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22])=[CH:13][C:12]=1[O:30][CH3:31]
Reactant: COc1cc(CCC(=O)CC(=O)c2ccccc2)ccc1OCC(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1cc(CCC(=O)CC(=O)c2ccccc2)ccc1OCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 5-(4-(2-boc-aminoethoxy)-3-methoxyphenyl)-1-phenylpentane-1,3-dione (211 mg, 0.48 mmol) dissolved in dioxane (5 ml) was added drop wise dry HCl in dioxane (4 M, 0.36 ml, 1.43 mmol) and stirred at RT for 1 h. After this time diethyl ether (20 ml) was added and an off-white emulsion was visible. The solvents were removed by evaporation in vacuo to give a brown gum residue. Residual dioxane was removed by azeotroping with methanol and then drying the product on high pressure line to give 5-(4-(2-aminoethoxy)-3-methoxyphenyl)-1-phenylpentane-1,3-dione hydrochloride (163 mg, 99%) as a brown powdery solid: mp 80° C.; LCMS 342 [M+H]+, 364 [M+Na]+, 1H NMR (400 MHz, MeOD) δ 2.79-2.82 (2H, m, CH2), 2.99-3.02 (2H, m, CH2), 3.33-3.34 (2H, m, NHCH2+solvent signal), 3.90 (3H, s, OCH3), 4.20 (2H, t, J=5.0 Hz, NHCH2CH2), 6.37 (1H, s, enol CH), 6.84-6.98 (3H, m, 3×ArH), 7.48-7.60 (3H, m, 3×ArH), 7.93 (2H, d, J=8.0 Hz, 2×ArH) ppm; 13C NMR (100 MHz, MeOD) δ 33.04, 41.40, 41.83, 57.31, 68.16, 98.35, 114.54, 117.51, 122.73, 128.84 (2×CH), 130.58 (2×CH), 134.34, 136.75, 137.93, 147.75, 151.73, 184.57, 198.44 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][OH:30])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:33]=1.N1C=CC=CC=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:33]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1)c1ccccc1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-1-{6-[2-(2-hydroxyethoxy)benzoylamino]-nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g )in pyridine (10 ml) is added with stirring methanesulfonyl chloride (0.1 ml) under ice-cooling, and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added water, and the precipitated crystals are collected by filtration, and dissolved in dichloromethane. The mixture is washed successively with diluted hydrochloric acid and water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is crystallized from diethyl ether to give 7-chloro-1-{6-[2-(2-methanesulfonyloxyethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.59 g) as white powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:19]=[N:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>CN(C=O)C>[CH2:3]([O:10][C:12]1[CH:19]=[N:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1ccncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccncc1OCc1ccccc1
Yield: 87 %

Procedure:
A mixture of 0.59 g of 60% sodium hydride (in oil) and 5 ml of DMF was stirred while ice-cooling. To the reaction mixture, 1.59 g of benzyl alcohol was added. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture, 2.0 g of 3-chloroisonicotinonitrile was added, and the reaction mixture was stirred at the same temperature for 30 minutes and at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and then to ethyl acetate was added to the reaction mixture, followed by filtration of insoluble matters. The filtrate was concentrated under reduced pressure and the resultant residue was subjected to silica gel column chromatography to give 2.64 g of 3-benzyloxy isonicotinonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:29]([CH2:30][CH2:31][OH:32])=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[CH2:25][CH2:24][C:8]2([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]3[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=3)=[O:15])[CH2:9]2)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:4][N:5]2[CH2:25][CH2:24][C:8]3([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]4[N:17]=[C:18]([CH:21]([CH3:22])[CH3:23])[S:19][CH:20]=4)=[O:15])[CH2:9]3)[CH2:7][CH2:6]2)=[CH:26][CH:27]=[CH:28][C:29]=1[CH2:30][CH:31]=[O:32]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4Cl)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CC=O)c4Cl)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (9-(2-chloro-3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 80, step e) (0.386 g) in DCM (5 mL) was cooled in ice-water, treated with trifluoroacetic acid (0.125 mL) and stirred for 5 minutes. Dess-Martin periodinane (0.519 g) was added, then the mixture was removed from the cooling bath and stirred at room temperature for 35 minutes. The solution was diluted with saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL) and the resulting mixture was stirred vigorously for 10 minutes. The mixture was then extracted twice with ethyl acetate, the combined organic phases were washed with brine, acidified with acetic acid (0.1 mL), dried over anhydrous magnesium sulphate and concentrated in vacuo to give the crude subtitled compound as a pale yellow gum. Yield 0.494 g.
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1.[F:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[S:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)[CH:39]=[CH:40][CH:41]=1>>[F:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[S:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:67])[CH3:68])[C:62]([OH:64])=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4cccc(F)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4cccc(F)c4)cc3)cc2C1=O
Yield: 93 %

Procedure:
The compound of example 56 was prepared analogous to compound of example 52 by hydrolysis of compound of example 55.
Reaction SMILES: ClC(=C(Cl)Cl)C([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(#N)C>CO>[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)C(Cl)=C(Cl)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: Nc1ccc(C(=O)O)cc1

Procedure:
N-Trichloroacryloyl-p-aminobenzoic acid (440 μg) was dissolved in 1 mL of methanol, and 100 μL of this solution was added to 300 μL of potassium phosphate buffer (0.1 M, pH 8). In the same way a solution of p-aminobenzoic acid was prepared. Both solutions were analyzed by HPLC (C18-silica column, 0.01 M potassium phosphate buffer pH 4.5 initially, then 0 to 38% acetonitrile over 29 minutes. This gave a retention time of 6.8 min for p-aminobenzoic acid and 26 min for the product. The solutions were kept at room temperature. Analysis by HPLC demonstrated that the N-trichloroacryloyl-p-aminobenzoic acid was stable at least for four days. By this last day the solution of the p-aminobenzoic acid had discolored and additional peaks were seen.