Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].CO[CH:14]=[CH:15][C:16]#[N:17].Cl>COCCOC.CCCCCC.C(OCC)(=O)C.O>[F:8][C:7]([F:10])([F:9])[C:6](=[O:11])[CH:5]=[CH:4][NH:3][CH:14]=[CH:15][C:16]#[N:17]
Reactant: COC=CC#N
Reactant: NC=CC(=O)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Solvent: O
Product: N#CC=CNC=CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 400 mg, 10 mmol) was charged and washed with hexane twice. Into this flask, 1,2-dimethoxyethane (20 ml) was added and then a solution prepared by dissolving 4-amino-1,1,1-trifluoro-3-buten-2-one (1.4 g, 10 mmol) and 3-methoxyacrylonitrile (830 mg, 10 mmol) in 1,2-dimethoxyethane (5 ml) was added dropwise under ice-cooling. After stirring the mixture at room temperature for 4 hours, the reaction mixture was poured into water (50 ml). This mixture was acidified with concentrated hydrochloric acid under ice-cooling and then extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/ethyl acetate=3/1 to 1/1) to obtain 593 mg (yield 31.2%) of title compound (IIa) having a low polarity and 680 mg (yield 35.8%) of title compound (IIb) having a high polarity.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(N(CC)CC)C>[CH2:8]([NH:2][C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: NC1(CO)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: OCC1(NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 40.6 %

Procedure:
To a mixture of 1-amino-1-cyclopropanemethanol hydrochloride (1.1 g), benzaldehyde (945 mg) and triethylamine (1.24 ml) in 1,2-dichloroethane (10 ml), sodium triacetoxyborohydride (5.66 g) was added with ice-cooling over 5 minutes. After being stirred at room temperature for 13 hours, the mixture was poured into aqueous sodium bicarbonate solution and stirred for several hours. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give 1-(N-benzylamino)-1-cyclopropanemethanol (641 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:10].[Cl-].C([NH2+]CCCC)CCC.[N+:21]([CH2:24][CH2:25]O)([O-:23])=[O:22].C([BH3-])#N>C(OC(=O)C)CC(C)C.CO.O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[C:3]=1[O:10][CH2:25][CH:24]([N+:21]([O-:23])=[O:22])[CH2:5]2
Reactant: O=[N+]([O-])CCO
Reactant: O=Cc1cccc(Br)c1O
Agent: CCCC[NH2+]CCCC
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Solvent: CC(=O)OCCC(C)C
Solvent: O
Product: O=[N+]([O-])C1COc2c(Br)cccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Commercially available 3-bromosalicylaldehyde (0.5 g; 2.5 mmol), di-n-butylammonium chloride (0.2 g; 1.2 mmol) and 2-nitroethanol (0.36 g; 4.0 mmol) were refluxed for 8 hours in i-pentylacetate with a Dean-Stark apparatus under nitrogen atmosphere. The solvent was evaporated and the product was dissolved in dichloromethane (15 ml) and cyanoborohydride (0.5 g; 8.1 mmol) in methanol (15 ml) was added. The mixture was stirred for 30 minutes at room temperature. Water was added and the mixture extracted with dichloromethane. The phase were separated and the organic layer was dried (MgSO4). The solvent was evaporated yielding 400 mg (63%) of 8-bromo-3-nitrochroman as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=[O:6].[Cl:23][CH2:24][CH:25]=O.C([BH3-])#N.[Na+].Cl>O.CO>[Cl:22][C:3]1[C:2]([NH:1][CH2:25][CH2:24][Cl:23])=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=[O:6]
Reactant: Nc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Reactant: O=CCCl
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc(NCCCl)c1Cl

Procedure:
Prepared according to the method described in Example 63 from 3-amino-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-yl)methylbenzamide from Example 54 (0.7 g), 50% chloroacetaldehyde in water (0.353 ml), sodium cyanoborohydride (0.159 g), 50% hydrochloric acid in methanol (0.385 ml) and methanol (10 ml), giving the subtitled compound as a white solid (0.777 g) after purification by flash column chromatography eluting with 3:1 iso-hexane:ethylacetate.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=2)[C:50]=1[CH3:67].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:67])[C:51]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=1)=[N:52]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of X-Phos (0.026 g, 0.055 mmol), 5-morpholinopyridin-3-amine (0.074 g, 0.413 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinoline (0.10 g, 0.344 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.013 g, 0.014 mmol) in toluene (3.44 mL) was added sodium t-butoxide (0.083 g, 0.86 mmol). The reaction mixture was heated to 120° C. and stirred for 45 min. The reaction was then cooled to rt and diluted with water (10 mL). The mixture was extracted with EtOAc (2×10 mL) and DCM (1×10 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on basic alumina (0 to 50% EtOAc in hexanes) to give the desired product 5,7-difluoro-3-methyl-N-(5-(4-morpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.70 (1H, d, J=4.5 Hz), 7.95 (1H, s), 7.78-7.92 (3H, m), 7.62 (1H, d, J=9.8 Hz), 7.33-7.43 (1H, m), 6.97-7.14 (2H, m), 6.60 (1H, br. s.), 3.79-3.94 (4H, m), 3.12-3.30 (4H, m), 2.16 (3H, s). Mass Spectrum (ESI) m/e=434.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C.[CH3:57][O:58][C:59]1[CH:60]=[C:61]([CH:63]=[CH:64][CH:65]=1)[NH2:62]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OC(=O)C)C.O.C1(C)C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:62][C:61]4[CH:63]=[CH:64][CH:65]=[C:59]([O:58][CH3:57])[CH:60]=4)[CH:3]=3)[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)=[CH:15][CH:16]=1
Reactant: NC1=NC(c2ccc(F)cc2)(c2cccc(Br)c2)CO1
Reactant: COc1cccc(N)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(Nc2cccc(C3(c4ccc(F)cc4)COC(N)=N3)c2)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A microwave tube was charged with 4-(3-bromo-phenyl)-4-(4-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (Building Block G 156 mg, 0.467 mmol, 1.0 eq), sodium tert-butoxide (89 mg, 0.933 mmol, 2.0 eq.), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1biphenyl (18 mg, 0.042 mmol, 0.042 eq.), tris(dibenzylideneacetone)dipalladium (10 mg, 0.012 mmol, 0.025 eq.) and 3-methoxyaniline (115 mg, 0.933 mmol, 2.0 eq.). After three vacuum-nitrogen cycles, toluene was introduced (1 mL), the tube was sealed and stirred at 100° C. for 16 hours. After cooling to room temperature, water (1 mL) and ethylacetate (1 mL) were added. The organic fraction of the reaction mixture was placed on an SCX column. This was then washed with dichloromethane/methanol. The desired product was obtained by eluting with 2 M ammonia in methanol. Fractions containing the compound were combined and the product purified further using preparative HPLC to yield 68 mg (40% yield) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Br:10]C1C(CBr)=NC(Cl)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][Br:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1Cl
Reactant: Clc1ccc(Br)c(CBr)n1
Product: Clc1ncc(Br)cc1CBr
Yield: 33 %

Procedure:
Compound 76B (0.46 g, 33%) was prepared from 76A (1.0 g, 4.9 mmol) using a procedure similar to the synthesis of 55B.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([CH:20]([CH3:23])[CH2:21][OH:22])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1.CCOC(C)=O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[C:14]4[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=4[N:12]([CH:20]([CH3:23])[CH2:21][OH:22])[CH:11]=3)=[O:9])[CH:3]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.7 %

Procedure:
To a mixture of (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 2, Preparation 26, 50 mg, 0.159 mmol) and 4-chlorophenylacetic acid (27.2 mg, 0.159 mmol) in pyridine (1 mL) was added HATU (121 mg, 0.31 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction was diluted with EtOAc, washed with saturated aqueous NaHCO3 solution, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using preparative TLC eluting with 7% MeOH in DCM to afford the title compound (28 mg).
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35]Cl)[CH:30]=1>CN(C)C=O>[Cl:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)[CH:30]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: ClCc1cc(Cl)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3cc(Cl)ccn3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Tetrahydrofuran (3 mL) and 5 N aqueous sodium hydroxide solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridine-3-yl)-isoxazole-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. Next, the reaction solution was concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 4-chloro-2-chloromethyl-pyridine (36.3 mg, 0.22 mmol) described in Manufacturing Example 51-1-2 was added to a suspension of this solid and N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This mixture was cooled to room temperature, and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (36.6 mg, 83%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:8]1[CH2:11][C:10]([C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)([F:12])[CH2:9]1)([CH3:7])[CH3:6])C.[BH4-].[Na+]>>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([C:10]4([F:12])[CH2:9][N:8]([C:5]([CH3:7])([CH3:6])[CH2:4][OH:3])[CH2:11]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: CCOC(=O)C(C)(C)N1CC(F)(c2nc3c(N4CCOCC4)nc(-n4c(CC)nc5ccccc54)nc3n2C)C1
Agent: [BH4-]
Agent: [Na+]
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(F)CN(C(C)(C)CO)C3)n(C)c2n1
Reaction time: 3 h
Yield: 56.2 %

Procedure:
To a solution of 2-{3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-fluoroazetidin-1-yl}-2-methylpropionic acid ethyl ester (40 mg, 0.07 mmol) in IMS (4 mL) was added NaBH4 (28 mg, 0.73 mmol) and the resulting mixture stirred at r.t for 3 h. Further NaBH4 (28 mg, 0.73 mmol) was added and the mixture stirred for a further 18 h. The reaction mixture was quenched with H2O, extracted with EtOAc and the organic phase dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) then dissolved in a mixture of MeCN and H2O and allowed to freeze-dry affording 850 as a white solid (20 mg, 54%). LCMS (method I): RT 2.64 min, [M+H]+ 509.4. 1H NMR (DMSO, 400 MHz): δ 8.05-8.04 (1 H, m), 7.64-7.63 (1 H, m), 7.26-7.25 (2 H, m), 4.58-4.49 (1 H, m), 4.44-4.14 (4 H, brd m), 4.08 (2 H, dd, J=18.70, 9.19 Hz), 3.81-3.74 (9 H, m), 3.28-3.26 (2 H, m), 3.19 (2 H, d, J=5.40 Hz), 1.34 (3 H, t, J=7.43 Hz), 0.91 (6 H, s)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH3:35][C@:36]([CH2:42][O:43][C:44]([F:47])([F:46])[F:45])([CH:40]=[CH2:41])[C:37]([OH:39])=[O:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1>[OH:32][C@@H:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2](/[CH:41]=[CH:40]/[C@:36]([CH3:35])([CH2:42][O:43][C:44]([F:45])([F:46])[F:47])[C:37]([OH:39])=[O:38])=[CH:3][CH:4]=3)[N:9]=2)[CH3:13])=[O:16])[NH:18]1)=[O:34])=[O:33]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=C[C@](C)(COC(F)(F)F)C(=O)O
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/[C@](C)(COC(F)(F)F)C(=O)O)cc3n2)N1
Temperature: 25 °C

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (212 mg, 0.4 mmol), crude (R)-2-methyl-2-trifluoromethoxymethyl-but-3-enoic acid (95 mg), tri(o-tolyl)phosphine (24 mg, 0.08 mmol) and triethylamine (121 mg, 0.17 mL, 1.2 mmol) in 1,4-dioxane (10 mL) was stirred at 50° C. under nitrogen. Trs(dibenzylideneacetone)dipalladium(0) (36 mg, 0.04 mmol) was added and the reaction mixture was heated at reflux for 40 minutes. The reaction mixture was cooled to room temperature and the mixture was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude (E)-(R)-4-{2-[(R)-1-({(S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carbonyl}-amino)-ethyl]-quinolin-7-yl}-2-methyl-2-trifluoromethoxymethyl-but-3-enoic acid which was used in the next step. LCMS (m/z) 652.1 [M+H], Tr=2.17 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([C:14]2[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][N:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:24])[C:3]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li+].[OH-].Cl.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:63][CH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67].C(N(C(C)C)CC)(C)C>O.O1CCCC1.[Cl-].[NH4+]>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([NH:63][CH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67])=[O:19])=[CH:16][N:15]=2)[CH2:10][CH:11]([CH3:12])[CH3:13])[CH:5]=[C:4]([CH3:24])[C:3]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][CH:26]=1
Reactant: COC(=O)CCN
Reactant: COC(=O)c1ccc(C(CC(C)C)Nc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)nc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Methyl 6-(1-(2,6-dimethyl-4′-(trifluoromethyl)biphenyl-4-ylamino)-3-methylbutyl)nicotinate (290 mg, 0.62 mmol) was dissolved in H2O (3 mL) and tetrahydrofuran (3 mL). The solution was cooled to 0° C. 1N LiOH (77.5 mg, 1.85 mmol) was added. The mixture was warmed to room temperature and stirred for 5 h. The mixture was then neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in N,N-dimethylformamide (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (338 mg, 0.888 mmol) was added and the mixture was stirred for 45 minutes. Methyl 3-aminopropanoate hydrochloride (123 mg, 0.888 mmol) and diisopropylethylamine (306 mg, 2.37 mmol) were added. The resulting mixture was stirred overnight at room temperature. The mixture was diluted with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to give methyl 3-(6-(1-(2,6-dimethyl-4′-(trifluoromethyl)biphenyl-4-ylamino)-3-methylbutyl)nicotinamido)propanoate. 1H NMR (400 MHz, CD3OD, δ): 8.88 (s, 1H), 8.10 (m, 1H), 7.64 (m, 3H), 7.23 (d, 2H), 6.31 (s, 2H), 4.55 (m, 1H), 3.65 (m, 5H), 2.65 (m, 2H), 1.82 (m, 6H), 1.60 (m, 1H), 1.0 (m, 6H).
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[C:7]1([NH:6][CH2:2][C:3]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccccc1
Solvent: O
Product: O=C(O)CNc1ccccc1

Procedure:
475 g of chloracetic acid (5 moles) are heated with 930 g aniline (10 moles) in 2 l water for 1.5 h to 100° C. After cooling, the N-phenylglycine formed is suctioned off and washed with water. Yield is 468 g (=62% with respect to the chloracetic acid).
Reaction SMILES: BrN1C(=O)CCC1=O.[N:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1.[OH:17][C:18]1[CH:19]=[C:20]([C:24]([NH2:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)(Cl)Cl.CN(C=O)C.C(Cl)Cl>[CH3:15][C:13]1[CH:12]=[C:11]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([C:24]([NH2:26])=[O:25])[CH:21]=[CH:22][CH:23]=2)[CH:10]=[N:9][CH:14]=1
Reactant: NC(=O)c1cccc(O)c1
Reactant: Cc1cncc(C)c1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cncc(COc2cccc(C(N)=O)c2)c1
Yield: 7.2 %

Procedure:
N-Bromosuccinimide (2.13 g, 12 mmol) and subsequently α,α′-azoisobutyronitrile (16 mg, 0.1 mmol) were added to a solution of 3,5-lutidine (1.14 ml, 10 mmol) in CCl4 (40 ml). The reaction mixture was stirred at reflux for 2 hrs. After cooling, succinimide was removed by filtration and the filtrate was evaporated to smaller volume (10 ml). To this filtrate, a mixture of 3-hydroxybenzenecarboxamide (550 mg, 4 mmol) and K2CO3 (830 mg, 6 mmol) in DMF (5 ml) was added and the new reaction mixture was stirred at 60° C. for 24 h. After diluting with CH2Cl2 (100 ml), the solution was washed with Na2CO3 solution (40 ml) and water (40 ml), dried (Na2SO4) and evaporated to dryness, under reduced pressure. The brown oil residue was extracted by trituration with Et2O (2×10 ml), and from the Et2O extracts, the precipitant solid was filtered and washed with pentane, to give 70 mg (7.2% yield) of the desired product. Mp 152-154° C., HPLC-MS: m/z 243 [M+H]+, Rt=2.28 min.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[N:4]1)[CH3:2].O1CCCC1.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[Cl:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[CH:31]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:44][C:43]1[CH:42]=[CH:41][C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[N:34]=3)[CH:31]=2)=[CH:23][C:22]=1[NH:21][C:8]([C:6]1[C:5]([CH3:11])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1)=[O:10]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Reactant: CCn1cc(C(=O)O)c(C)n1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CCn1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2Cl)c(C)n1
Yield: 42.7 %

Procedure:
In the same manner as in Example 55 and using 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (56.5 mg, 0.366 mmol), tetrahydrofuran (5 mL), thionyl chloride (63.3 μL, 0.730 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-chlorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (114 mg, 0.332 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (68.0 mg, 43%) was obtained as a white solid.
Reaction SMILES: C(OCCCCC)(=O)C.[OH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[ClH:28].[N:31]1([CH2:30][CH2:29][O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: ClCCN1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCOC(C)=O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Reaction time: 1 h
Yield: 91 %

Procedure:
To a 2000 gallon reaction tank were added: 1320L of amyl acetate, 167.42 kg of methyl 4-hydroxybenzoate, 408.6 kg of anhydrous potassium carbonate, and 283.5 kg of β-chloroethylpiperidine hydrochloride. The mixture was heated to 120° C.–125° C. for 5 hours, at which time HPLC analysis indicated complete consumption of the methyl 4-hydroxybenzoate. The tank was cooled to less than 50° C. 880L of deionized water were added to the tank. The layers were separated and the aqueous layer was discarded. In a glass-lined tank was mixed 367 liters of food grade hydrochloric acid and 184L of deionized water. The acid mixture was combined with the organic layer. The layers were separated and the organic layer was discarded. The mixture of the intermediate ester in aqueous acid heated to reflux until HPLC suggested no further consumption of the ester (13 hours). The mixture was cooled to less than 40° C., 550 liters of acetone was added to the mixture and the mixture was cooled to 0° C.–5° C. and stirred for 1 hour. The product was collected by filtration on a centrifuge. The wet cake was rinsed on the centrifuge with 400L of acetone. The product was dried in a rotary vacuum (double cone) dryer at less than 50° C. and 25–27 inches in mercury. Yield was 91% of theoretical.