Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)COC1C(Br)=CC(Cl)=CN=1)(C)(C)C.Br[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][CH2:27][O:28][CH3:29].[C:30]([C:32]1[CH:37]=[C:36]([S:38]([CH2:41][CH2:42][CH3:43])(=[O:40])=[O:39])[CH:35]=[CH:34][C:33]=1[CH3:44])#[CH:31]>>[CH2:41]([S:38]([C:36]1[CH:35]=[CH:34][C:33]([CH3:44])=[C:32]([C:30]#[C:31][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][O:28][CH3:29])[CH:37]=1)(=[O:39])=[O:40])[CH2:42][CH3:43]
Reactant: COCOc1ccc(Cl)cc1Br
Reactant: C#Cc1cc(S(=O)(=O)CCC)ccc1C
Agent: CC(C)(C)OC(=O)COc1ncc(Cl)cc1Br
Product: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCOC)c1
Yield: 70 %

Procedure:
Following the general method as outlined in Intermediate 183, starting from 2-bromo-4-chloro-1-(methoxymethoxy)benzene (Intermediate 265) and 2-ethynyl-1-methyl-4-(propane-1-sulfonyl)-benzene (Intermediate 40), the title compound was obtained as a white solid in 70% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH:24]5[CH2:27][O:26][CH2:25]5)[CH2:20][CH2:19]4)[CH:16]=3)[CH2:11][C@@H:10]2[OH:28])=[O:7])=[CH:4][CH:3]=1.N1(C2C=CN=CC=2)CCCC1.[CH3:42][N:43]=[C:44]=[O:45]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:18]4[CH2:19][CH2:20][N:21]([CH:24]5[CH2:27][O:26][CH2:25]5)[CH2:22][CH2:23]4)[CH:16]=3)[CH2:11][C@@H:10]2[O:28][C:44](=[O:45])[NH:43][CH3:42])=[O:7])=[CH:29][CH:30]=1
Reactant: O=C(N[C@H]1c2cc(N3CCN(C4COC4)CC3)ccc2C[C@@H]1O)c1ccc(F)cc1
Reactant: CN=C=O
Agent: c1cc(N2CCCC2)ccn1
Solvent: C1CCOC1
Product: CNC(=O)O[C@H]1Cc2ccc(N3CCN(C4COC4)CC3)cc2[C@@H]1NC(=O)c1ccc(F)cc1
Yield: 79.8 %

Procedure:
To a solution of 4-fluoro-N-[(1S,2S)-2-hydroxy-6-[4-(oxetan-3-yl)piperazin-1-yl]indan-1-yl]benzamide (220 mg, 0.535 mmol) in tetrahydrofuran (3.0 mL) add 4-pyrrolidinopyridine (16 mg, 0.107 mmol) and seal in a pressure vial. Add methyl isocyanate (97 μL, 1.60 mmol) by syringe to the mixture and stir at 60° C. overnight. Cool the resulting suspension in an ice bath, collect the white solid by filtration, and dry in a vacuum oven at 40° C. for 3 hr. to obtain the title compound (200 mg, 80%). LC-ES/MS m/z 469 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:16]3(C(O)=O)[CH2:18][CH2:17]3)[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1(P([N:36]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1COCC1>[NH2:36][C:16]1([C:12]2[CH:11]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)[CH:15]=[N:14][CH:13]=2)[CH2:18][CH2:17]1
Reactant: N#Cc1ccc(-c2cncc(C3(C(=O)O)CC3)c2)cc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cncc(C3(N)CC3)c2)cc1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)cyclopropanecarboxylic acid (900 mg, 3.01 mmol) in toluene (50 mL) was added TEA (0.63 mL, 4.52 mmol) and diphenylphosphoryl azide (0.977 mL, 4.52 mmol), and the mixture was heated to 100° C. for 4 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was re-dissolved in THF (100 mL) and a solution of KOtBu (2.03 g, 18.08 mmol) in THF (40 mL) was added. The mixture was stirred at 0° C. for 1 h. The mixture was then warmed to room temperature overnight. Silica gel (10 g) was added and the mixture was concentrated in vacuo. The residue was purified by silica chromatography eluting with a 0-10% MeOH-DCM gradient to give 4-(5-(1-aminocyclopropyl)pyridin-3-yl)-2-chlorobenzonitrile. m/z 270.0, 272.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:11]2([OH:24])[CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1>[Pd].C(O)=O>[F:34][C:32]([F:33])([F:35])[O:31][C:28]1[CH:27]=[CH:26][C:25]([CH:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:37])([F:1])[F:36])=[CH:5][CH:6]=2)[C:11]2([OH:24])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:30][CH:29]=1
Reactant: OC1(C(c2ccc(OC(F)(F)F)cc2)c2ccc(OC(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: O=CO
Product: OC1(C(c2ccc(OC(F)(F)F)cc2)c2ccc(OC(F)(F)F)cc2)CCNCC1

Procedure:
In the first step as depicted in Scheme 4, two appropriately substituted aryl halides, for example, the known compound 4-bromo-1-(trifluoromethoxy)benzene (A3), were cross-coupled with a Grignard reagent and an alkyl formate, for example, ethyl formate to form bis[4-(trifluoromethoxy)phenyl]methan-1-ol (B3). Intermediate (B3) was then reacted under acidic conditions with hydrogen bromide, to afford the corresponding bis(trifluoromethoxyphenyl)bromomethane (C3). Intermediate (C3) was then lithiated, for example with butyl lithium, and then reacted with an appropriately N-substituted piperidin-4-one, formula (D3), for example 1-benzylpiperidin-4-one, at a temperature in the range of −85° C. to −60° C. to afford the corresponding 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-benzylpiperidin-4-ol (E3). Intermediate (E3) was then reacted with an acid, for example formic acid, in the presence of a catalyst, for example a palladium catalyst, to form the hydrogen chloride salt of 4-{bis[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-ol (F3). Next, an appropriately substituted phenol, for example, the known compound 4-hydroxybenzaldehyde, was cross-coupled with a halopyridine, for example 2-chloropyridine, in the presence of potassium carbonate and a catalytic amount of copper oxide at a temperature in the range of 145° C. to 170° C. to form 4-(2-pyridyloxy)benzaldehyde (G3). Intermediate (F3) was then cross-coupled with Intermediate (G3) in the presence of sodium triacetoxyborohydride to form 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-[(4-(2-pyridyloxy)phenyl)methyl]piperidin-4-ol (I-A). Intermediate (I-A) was then oxidized with hydrogen peroxide at a temperature in the range of 40° C. to 55° C. to form a compound of formula I-C.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.[C:11](=[S:13])=[S:12].[OH-].[K+].Cl>C(O)C>[Cl:10][C:9]1[C:2]2[NH:1][C:11](=[S:12])[S:13][CH2:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: S=C=S
Reactant: Nc1c(Cl)cccc1CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: S=C1Nc2c(Cl)cccc2CS1

Procedure:
A 9 g. portion of 2-amino-3-chlorobenzyl alcohol was combined with 15 ml. of carbon disulfide and 5 g. of potassium hydroxide in 100 ml. of ethanol. The reaction mixture was stirred at reflux temperature overnight, and was then dumped into ice. After the aqueous mixture was acidified with hydrochloric acid, the product was extracted from the mixture with methylene chloride and was purified by chromatography over alumina with chloroform-hexane as the eluent. After recrystallization from methanol, 3,2 g. of 8-chloro-1,4-dihydro-2H-3,1-benzothiazin-2-thione, m.p. 125°-126° C., was obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=1.[ClH:32].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:32].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:29](=[O:30])[C:26]4[CH:27]=[CH:28][C:23]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=5)=[CH:24][CH:25]=4)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccccn4)cc3)cn12

Procedure:
The title compound was obtained as white solid by conducting the operations similar to those of Example 1, using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 4-(2-pyridyl)benzenecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure, to provide the title compound as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[I-].[Na+].[CH2:15](Br)[C:16]#[CH:17].C(N(C(C)C)C(C)C)C>CC(C)=O>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:17][C:16]#[CH:15])=[CH:9][C:6]=1[CH:7]=[O:8])([O-:12])=[O:11]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: C#CCBr
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A mixture of 25 g (150 mmol) 5-hydroxy-2-nitro-benzaldehyde, 44.9 g (299 mmol) sodium iodide, 44.5 g propargyl bromide (80% in toluene), 42 ml N-ethyl-diisopropy-lamine and 400 ml acetone is stirred at rt for 6 d. The reaction mixture is filtered, concentrated, taken up in 1M aqueous hydrochloric acid and extracted with ethyl acetate to yield 2-nitro-5-propargyloxy-benzaldehyde.
Reaction SMILES: [CH2:1]([N:5]([C:12]1[C:17](I)=[CH:16][C:15]([F:19])=[CH:14][N:13]=1)C(=O)C(F)(F)F)[CH:2]=[CH:3][CH3:4]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:3]([C:2]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:19])[CH:16]=2)[NH:5][CH:1]=1)[CH3:4]
Reactant: CC=CCN(C(=O)C(F)(F)F)c1ncc(F)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1c[nH]c2ncc(F)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
A solution of N-but-2-enyl-2,2,2-trifluoro-N-(5-fluoro-3-iodo-pyridin-2-yl)-acetamide (2.57 g, 6.5 mmol) in DMF (10 mL) is treated with n-Bu4NCl (2 g, 7.15 mmol), Pd(OAc)2 (59 mg, 0.26 mmol), and stirred at 100° C. for 2 h. The mixture is cooled to rt, diluted with EtOAc (50 mL), filtered through a pad of silica gel, and washed with 1 M HCl (50 mL). The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 25%-70% EtOAc in heptane to afford 3-ethyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine (0.75 g, 70%). MS: 165 (M+H); 1H NMR (300 MHz, CDCl3): δ 9.62 (s, NH, 1H), 8.17 (m, 1H), 7.60 (m, 1H), 7.16 (s, 1H), 2.74 (q, 2H), 1.31 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[N+:19]([O-:21])=[O:20])[C:3]=1[C:22]([O:24][CH3:25])=[O:23].[H-].[Na+].CI.[C:30](OCC)(=O)C>O1CCCC1.CC(CC(C)=O)C.CCCCCC>[CH3:1][C:2]1[N:7]([CH3:30])[C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCCCCC
Solvent: CC(=O)CC(C)C
Product: COC(=O)C1=C(C)N(C)C(C)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Temperature: 88 °C
Reaction time: 1 h

Procedure:
12 g of nifedipine was dissolved in 50 ml of tetrahydrofuran under a nitrogen atmosphere. 1.66 g of a sodium hydride/oil dispersion (60% NaH) was added. Following agitation for some time, 10 ml of methyl iodide was added, and the resulting mixture was agitated for 1 hour at 88° C. 200 ml of ethyl acetate was then added. The resulting organic layer was washed several times with water, and was then dehydrated with sodium sulfate. The sodium sulfate was filtered out, and the solvent was removed from the filtrate by means of a rotary evaporator. The solid obtained was dissolved in 200 ml of MIBK, and hexane was added to this, producing 8.9 g of N-methylnifedipine in the form of yellow crystals. This compound had a melting point of 184 to 187° C., infrared absorption spectrum of 1690 cm-1 : C=O, 1524 cm-1 : N--O, and proton-NMR spectrum (solvent: CDCl3): 2.5 (6H, methyl), 3.3 (3H, N-methyl), 3.6 (6H, O-methyl), 5.7 (1H, C--H), 7.2-7.6 (4H, C--H in aromatic nucleus).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=2[C:19]([OH:21])=O)=[CH:5][CH:4]=1.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[O:26]=[C:25]1[CH:24]([N:23]2[C:19](=[O:21])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:13]2=[O:15])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NC1CCC(=O)NC1=O
Reactant: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Yield: 84 %

Procedure:
A mixture of 3-(4-methoxyphenylamino)phthalic acid (0.52 g, 1.8 mmol) and rac-α-aminoglutarimide hydrochloride (0.30 g, 1.8 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed in 95:5 methylene chloride-methanol, eluting 0.58 g of the product, in 84% yield: mp 228-230° C.; 1H NMR (DMSO-d6) δ 2.04-2.09 (m, 1H), 2.52-2.64 (m, 2H), 2.83-2.96 (m, 1H), 3.77 (s, 3H), 5.12 (dd, J=12.6 Hz, J=5.4 Hz, 1H), 6.96-7.00 (m, 2H), 7.12-7.17 (m, 2H), 7.24-7.28 (m, 2H), 7.54 (t, J=7.9 Hz, 1H), 8.24 (s, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 31.0, 48.7, 55.3, 110.6, 112.4, 114.7, 118.5, 125.3, 131.8, 132.4, 136.1, 144.3, 156.6, 167.1, 168.4, 170.0, 172.8; Anal. calcd for C20H17N3O5: C, 63.32; H, 4.52; N, 11.08. Found: C, 63.31; H, 4.47; N, 10.83.
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([C@@H:7]2[O:11][C@H:10]([CH2:12][O:13][P:14]([O:17][P:18]([O:21][CH2:22][C@H:23]3[O:27][C@@H:26]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH2:37])[C:31]=5[N:30]=[CH:29]4)[C@H:25]([O:38][P:39]([OH:42])([OH:41])=[O:40])[C@@H:24]3[OH:43])([OH:20])=[O:19])([OH:16])=[O:15])[C@@H:9]([OH:44])[C@H:8]2[OH:45])[CH:4]=[C:3]([C:46]([NH2:48])=[O:47])[CH:2]=1.O=C[C@H]([C@@H]([C@@H]([C@H](C)O)O)O)O>>[CH:34]1[N:35]=[C:36]([NH2:37])[C:31]2[N:30]=[CH:29][N:28]([C@@H:26]3[O:27][C@H:23]([CH2:22][O:21][P:18]([O:17][P:14]([O:13][CH2:12][C@H:10]4[O:11][C@@H:7]([N:5]5[CH:4]=[C:3]([C:46]([NH2:48])=[O:47])[CH2:2][CH:1]=[CH:6]5)[C@H:8]([OH:45])[C@@H:9]4[OH:44])([OH:16])=[O:15])([OH:20])=[O:19])[C@@H:24]([OH:43])[C@H:25]3[O:38][P:39]([OH:42])([OH:41])=[O:40])[C:32]=2[N:33]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reaction time: 0.08 h

Procedure:
To 2.5 ml of Tris-imidazole-sodium acetate buffer solution (solution containing 0.12 M each is adjusted to pH of 9.5 with 4 N NaOH) is added 0.2 ml of 15 mM NADP+ solution After keeping at 37° C. for 5 minutes, 0.1 ml of an enzyme solution is added and 0.2 ml of 150 mM L-fucose solution is further added to the system to initiate the reaction. Immediately thereafter, the reaction mixture is transferred to a cell for measurement of absorbance (1 cm light path) kept at 37° C. and absorbance is measured at the wavelength of 340 nm for 2 minutes or, if necessary, over a longer time period. One unit is an amount of enzyme that produces 1 μmole of NADPH for one minute.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15](O)=[O:16].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>>[Br:11][C:12]1[CH:13]=[C:14]([C:15]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)=[O:16])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: c1cc2c(cn1)NCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(=O)N2CCOc3ccncc32)cc1Br
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a mixture of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (50 mg, 0.37 mmol) and 3-bromo-4-methoxy-benzoic acid (102 mg, 0.44 mmol), phosphorus oxychloride (2 ml) was added and stirred at 100° C. for 12 hours. The reaction mixture was cooled to 0° C., neutralized with saturated solution of sodium hydrogen carbonate to pH of 8-9 and extracted with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:42][CH:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:28])[N:48]3[CH2:49][CH2:50][N:45]([CH:43]([CH3:44])[CH3:42])[CH2:46][CH2:47]3)[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CC(C)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10 mL) was added DIEA (126 mg, 0.97 mmol), 1-(propan-2-yl)piperazine (126 mg, 0.98 mmol) and HATU (185 mg, 0.49 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product (200 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=40:60 within 14 min; Detector, UV 254 nm. This resulted in 51.6 mg (28%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(propan-2-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 20) [M+H]+=573.2, RT=1.80 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.2, 6.9 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 9.0 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.52-3.48 (m, 4H), 2.78-2.65 (m, 1H), 2.46-2.39 (m, 4H), 1.09-0.97 (d, 6H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]([NH:19][CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:21]=O>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]([N:19]([CH3:21])[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Reactant: C=O
Solvent: O=CO
Product: CN(C)C1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1

Procedure:
Referring to Scheme 1, the beta-tetralone analog 5 is derived from the alpha-tetralone 1 in four steps. The reduced ketone (Compound 2) is dehydrated and the resultant alkene (Compound 3) is converted to the diol (Compound 4). Elimination of water from the diol gives the beta-tetralone (Compound 5). Compound 5 is then condensed with ammonium chloride under reductive amination conditions to give Compound 6, a compound of the invention (e.g., using the preferred 3,4-dichorophenyl as an example, to give [4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-amine). Alternatively, compound 5 is condensed with methylamine hydrochloride under the same conditions to give a compound of the invention, [4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-methyl-amine (Compound 7). Additionally, the monomethyl amine (Compound 7) can be further elaborated under Eschweiler-Clark conditions (using formic acid (HCO2H) and formaldehyde (HCHO)) to give a compound of the invention, [4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-dimethyl-amine (Compound 8). Compounds 6, 7, or 8 may be synthesized as a mixture of racemic cis and trans, or may be separated to give an enantiomerically enriched or an enantiomerically pure form of one of its four isomers. Cis and trans assignments may be made using methods known in the art (e.g., on the basis of NMR coupling patterns). The absolute configuration can, for instance, be determined by synthesis from a precursor of known configuration, or by X-ray crystallographic determination using a suitable crystal of the compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=[C:4]([NH2:24])[N:3]=1.[F:25][C:26]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH2:24][C:4]1[N:3]=[C:2]([C:32]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:25])[CH:33]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=1
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc4cc(Cl)ccc4[nH]3)C2)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
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
Solvent: O
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc5cc(Cl)ccc5[nH]4)C3)nc(N)n2)cc1F
Yield: 56.8 %

Procedure:
To a suspension of 4-chloro-6-(2-(5-chloro-1H-benzo[d]imidazol-2-yl)morpholino)pyrimidin-2-amine (200 mg, 0.548 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (176 mg, 0.712 mmol) and Na2CO3 (145 mg, 1.369 mmol) in 1,4-dioxane (2.4 mL) and water (0.8 mL) under nitrogen was added Pd(PPh3)4 (63.3 mg, 0.055 mmol). The reaction vessel was sealed and heated in Biotage Initiator using initial high to 140° C. for 1 hour. The reaction mixture was partitioned between EtOAc/THF (25/25 mL) and water (50 mL). The organic phase was washed with water (50 m, dried (Na2SO4) and evaporated in vacuo. The residue was triturated with EtOAc (1×10 mL). The resulting solid was filtered through a coarse fritted glass funnel and collected to afford the title compound (140 mg). LC-MS (ES) m/z=450 [M+H]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[C:17]2=[CH:18][O:19][N:20]=[C:16]2[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:14]([CH2:28][OH:29])[CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[C:17]2=[CH:18][O:19][N:20]=[C:16]2[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:14]([CH:28]=[O:29])[CH:13]=1
Reactant: OCc1cc(Cl)c2conc2c1-c1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cc(Cl)c2conc2c1-c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
Dimethyl sulfoxide (0.064 mL, 0.90 mmol) was added to oxalyl chloride (0.048 mL, 0.56 mmol) in methylene chloride (2.1 mL) at −78° C. After 10 minutes, [4-chloro-7-(3-fluorophenyl)-2,1-benzisoxazol-6-yl]methanol (0.104 g, 0.374 mmol) in methylene chloride (4.2 mL) was added and the resulting mixture was stirred at −78° C. for 30 minutes. Triethylamine (0.261 mL, 1.87 mmol) was then added and the mixture was stirred for 5 hours at room temperature. After quenching with water, the mixture was extracted with methylene chloride. The organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated to dryness. The resulting mixture was purified on silica gel, eluting with 0 to 30% ethyl acetate in hexane, to give the desired product (88 mg, 85%). LCMS calculated for C14H8ClFNO2 (M+H)+: m/z=276.0; Found: 276.1.