Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([NH2:6])[CH:3]=[N:2]1.C(OC([NH:14][C:15]1[S:19][C:18]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[N:17][C:16]=1[C:28](O)=[O:29])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:14][C:15]1[S:19][C:18]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[N:17][C:16]=1[C:28]([NH:6][C:4]1[CH:5]=[N:1][NH:2][CH:3]=1)=[O:29]
Reactant: Nc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cn[nH]c1
Yield: 78 %

Procedure:
Following the procedures as described in Example 113, 1H-pyrazol-4-amine, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid and HATU were reacted to give 101 as a white solid (63 mg, 78%) over two steps. 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 9.71 (s, 1H), 7.95 (s, 1H), 7.74 (s, 1H), 7.65-7.44 (m, 1H), 7.27 (t, J=8.4, 2H). ESIMS m/z=322.0 (M+1)
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][NH:10][N:9]=1.Cl[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>O1CCOCC1>[NH2:7][C:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:9]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: Clc1ncccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2ncccn2)nc1N
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Potassium tert-butoxide (2.4 g, 21.23 mmol) is added to a mixture of ethyl 3-amino-1H-pyrazole-4-carboxylate (3.0 g, 19.3 mmol) and 2-chloropyrimidine (2.2 g, 19.3 mmol) in 50 mL of anhydrous dioxane. The reaction mixture is heated to 100° C. and stirred for 2 h. The solvent is removed in vacuo, and the residue is partitioned between EtOAc and water (50 mL each). The aqueous layer is extracted two more times with EtOAc (40 mL each), and the combined organic extracts are dried (Na2SO4), filtered, and evaporated in vacuo to give a yellow/brown oily solid. This crude product is triturated with EtOAc to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:9]([Cl:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[CH:4]=O.[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[OH-].[K+]>CN(C=O)C.O>[CH3:19][O:18][C:16]([C:15]1[S:14][C:2]2[C:9]([Cl:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=2[CH:4]=1)=[O:17]
Reactant: COC(=O)CS
Reactant: O=Cc1cc([N+](=O)[O-])cc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cc([N+](=O)[O-])cc(Cl)c2s1
Reaction time: 2 h

Procedure:
To a solution of 2,3-dichloro-5-nitrobenzaldehyde (10 g, 0.045 mol) and methyl mercaptoacetate (6.6 mL, 0.06 mol) in DMF (200 mL) was added KOH (6 g) in 50 mL water. After stirring for 2 h, the reaction mixture was poured in ice cold water and the mixture was extracted in ethyl acetate. The organic layer was washed with water and dried. The evaporation of the solvent gave crude product which was purified by repetitive washing with hexane to yield 7-chloro-5-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester, 12.3 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][C:12](=[CH2:14])[CH2:11][CH:10]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[Cl:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1>C1COCC1.CCN(CC)CC>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:13][C:12](=[CH2:14])[CH2:11][CH:10]1[C:15](=[O:17])[NH:45][C:44]1[CH:46]=[CH:47][C:41]([Cl:40])=[CH:42][CH:43]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C1CC(NC(=O)OC(C)(C)C)C(C(=O)O)C1
Reactant: Nc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C1CC(NC(=O)OC(C)(C)C)C(C(=O)Nc2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 64 %

Procedure:
A stirred solution of 1.085 g of 35b in 10 ml of THF was treated subsequently with 1.25 ml of NEt3, 0.69 g hydroxybenzotriazole, 1.21 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 0.63 g of 4-chloroaniline and stirring was continued at 22° C. for 16 h. The mixture was evaporated and the residue partitioned between CH2Cl2 and 1 N HCl. The separated organic layer consisting of a white suspension was filtered and the residue dried to give 1.01 g (64%) of the title compound 35c. MS: 351.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[C:36]([F:40])=[CH:37][CH:38]=[CH:39][C:32]=3[Cl:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1cccc(Cl)c1CBr
Product: Cc1nc2c(ccn2Cc2c(F)cccc2Cl)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-chloro-6-fluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.48-7.40 (m, 1 H), 7.33-7.27 (m, 2 H), 7.23-7.17 (m, 1 H), 7.10-7.03 (m, 1 H), 7.00-6.95 (m, 1 H), 6.91 (t, J=7.7 Hz, 1 H), 6.21-6.14 (m, 1 H), 5.72-5.55 (m, 3 H), 4.31-4.24 (m, 2 H), 2.92-2.77 (m, 2 H), 2.74 (s, 3 H), 2.06 (s, 2 H), 1.02-0.92 (s, 9 H); LC/MS (m/z) ES+=537.38 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)[CH:23]=2)[CH:7]=[C:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:4]2[CH:23]=[C:22]([CH:21]=[C:6]([CH:7]=[C:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)[CH:5]=2)[O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][N:26]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cc(Oc3ccc(C(F)(F)F)cn3)cc(C3CC3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(Oc2cc(C=C3CCNCC3)cc(C3CC3)c2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of tert-butyl 4-(3-cyclopropyl-5-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.408 g, 0.859 mmol) in dry CH2Cl2 (5 mL) was added trifluoroacetic acid (1.0 mL, 13.05 mmol) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and at RT for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (0.270 g, 84%) which was used in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH:17](Br)([CH3:19])[CH3:18]>>[CH:17]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=2)[CH2:13][CH2:12]1)([CH3:19])[CH3:18]
Reactant: Cc1ccc(N2CCNCC2)cc1[N+](=O)[O-]
Reactant: CC(C)Br
Product: Cc1ccc(N2CCN(C(C)C)CC2)cc1[N+](=O)[O-]

Procedure:
Beginning with 1-(4-methyl-3-nitro-phenyl)-piperazine and 1-isopropylbromide, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 263 (M+, 31), 249 (15), 248 (bp), 84 (15), 56 (42).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31](F)([F:33])F)#[N:2].S(Cl)(Cl)=O.C[N:40](C=O)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][C:27]([NH2:40])=[O:29])=[CH:22][CH:23]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[CH2:31][F:33])#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(=O)O)cc3)C2=S)cc1C(F)(F)F
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(N)=O)cc3)C2=S)cc1CF
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7 -diazaspiro[3.4]octan-5-yl)phenyl)butanoic acid, RD141 (Formula 51) (60 mg, 0.12 mmol) in DMF (3 mL) was added thionyl chloride (0.01 mL, 0.15 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. Then ammonia was bubbled into the mixture. The mixture was partitioned with ethyl acetate (25 mL) and water (25 mL). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 70:30) to yield 4-(4-(7-(4-Cyano-3 -(fluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanamide, RD130 (Formula 52) (37 mg, 61%) as a white powder. 1H NMR δ 7.97 (d, 1H, J=1.8 Hz), 7.95 (d, 1H, J=8.3 Hz), 7.85 (dd, 1H, J=8.3 Hz), 7.39 (d, 2H, J=8.3 Hz), 7.22 (d, 2H, J=8.3 Hz), 5.59 (br s, 2H), 2.77 (t, 2H, J=7.5 Hz), 2.62-2.68 (m, 2H), 2.51-2.59 (m, 2H), 2.31 (t, 2H, J=7.5 Hz), 2.16-2.25 (m, 1H), 2.05 (p, 2H, J=7.5 Hz), 1.57-1.70 (m, 1H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([NH:13][CH:14]2[CH:21]3[CH2:22][C:17]4([C:24]([O:26]C)=[O:25])[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)=[O:12])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([NH:13][CH:14]2[CH:15]3[CH2:16][C:17]4([C:24]([OH:26])=[O:25])[CH2:18][CH:19]([CH2:20][CH:21]2[CH2:22]4)[CH2:23]3)=[O:12])[CH2:3][CH2:2]1
Reactant: COC(=O)C12CC3CC(C1)C(NC(=O)N1CCOc4ccccc41)C(C3)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC1C2CC3CC1CC(C(=O)O)(C3)C2)N1CCOc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of methyl 4-[(2,3-dihydro-4H-1,4-benzoxazin-4-ylcarbonyl)amino]adamantane-1-carboxylate obtained in Example 35 (a mixture of Compounds 35a and 35b, 474 mg) in tetrahydrofuran (6 ml), 1M aqueous sodium hydroxide (6 ml) was added and heated under reflux for 3 hours. After cooling at room temperature, the reaction mixture was adjusted to pH 1 to 2 by dropwise addition of 1M aqueous hydrochloric acid under ice cooling, and then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure to give an isomer mixture of the titled compounds (a mixture of Compounds 36a and 36b, 469 mg) as a light-pink powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]([CH3:22])[C:20]#[N:21])[CH:15]=[CH:16][C:17]=1O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:17]3[CH:16]=[CH:15][C:14]([CH:19]([CH3:22])[C:20]#[N:21])=[CH:13][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CC(C#N)c1ccc2oc(Nc3ccc(Cl)cc3)nc2c1

Procedure:
4-chlorophenylisocyanate (3.1 g.) was slowly added to a stirred solution of 2-(3-amino-4-hydroxyphenyl propionitrile (3.3 g.) in xylene (35 ml.) at room temperature. When the addition was complete p-toluenesulphonic acid (250 mg.) was added, and the solution was heated under reflux using a Dean and Stark apparatus. On cooling, the solution was washed with aqueous sodium bicarbonate solution and evaporated to dryness. The residue was recrystallised to give 2-[2-(4-chloroanilino)-5-benzoxazolyl]propionitrile as a creme solid which was characterised by n.m.r. spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]=[O:13])[O:8][CH2:7][CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5]2.[BH4-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][OH:13])[O:8][CH2:7][CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5]2
Reactant: CCCCCC1COc2cc(C=O)c(F)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCC1COc2cc(CO)c(F)cc2C1
Reaction time: 3 h

Procedure:
11.1 g (44.3 mmol) of 6-fluoro-3-pentylchroman-7-carbaldehyde are dissolved in 100 ml of ethanol, and 2.0 g (52.8 mmol) of sodium borohydride are added in portions. After 3 h, the batch is diluted with water and extracted three times with MTB ether. The combined org. phases are washed with sat. sodium chloride soln. and dried over sodium sulfate, the solvent is removed in vacuo, and the residue is filtered through silica gel with dichloromethane (Rf=0.3), giving (6-fluoro-3-pentylchroman-7-yl)methanol as a colourless solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[NH:26][C:9]2[CH2:10][C@@:11]3([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)[C@H:16]([CH2:17][C:8]=2[C:7]=1[CH3:27])[CH2:15][NH:14][CH2:13][CH2:12]3)=[O:5])[CH3:2].[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH:35]=O.C([BH3-])#N.[Na+].[ClH:41]>CO.C(O)(=O)C>[ClH:41].[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[NH:26][C:9]2[CH2:10][C@@:11]3([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)[C@H:16]([CH2:17][C:8]=2[C:7]=1[CH3:27])[CH2:15][N:14]([CH2:35][C:31]1[O:30][CH:34]=[CH:33][CH:32]=1)[CH2:13][CH2:12]3)=[O:5])[CH3:29]
Reactant: O=Cc1ccco1
Reactant: CCN(CC)C(=O)c1[nH]c2c(c1C)C[C@@H]1CNCC[C@@]1(c1cccc(OC)c1)C2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1[nH]c2c(c1C)C[C@@H]1CN(Cc3ccco3)CC[C@@]1(c1cccc(OC)c1)C2
Temperature: 0 °C
Reaction time: 15 h

Procedure:
1.3 g (3.3 mmol) of (±)-trans-2-diethylaminocarbonyl-8a-(3-methoxyphenyl)-3-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline, 0.28 ml (4.95 mmol) of acetic acid, 0.33 ml (3.96 mmol) of 2-furaldehyde were dissolved in 50 ml of MeOH under nitrogen atmosphere. 0.415 g (6.6 mmol) of sodium cyanoborohydride were added and the solution stirred for 15 h. Additional acetic acid (0.1 ml), 2-furaldehyde (0.3 ml) and sodium cyanoborohydride (0.2 g) were added. After two hours of stirring the reaction mixture was cooled to 0° C. and 50 ml of 5N hydrochloric acid were added. The solvent was removed in vacuo, the aqueous solution was extracted with Et2O, the pH was adjusted to 8 with 20% NaOH and then extracted with AcOEt. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was dissolved in acetone/MeOH and the solution brought to acidic pH with HCl/Et2O . The precipitate was filtered, yielding 1.7 g of the title compound. M.p.=105° C. dec.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([CH2:24][N:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])[CH:23]=2)[O:20][C:19]([CH3:31])([CH3:30])[CH2:18][C:17]3([CH3:33])[CH3:32])=[CH:8][CH:7]=1)[CH3:5].[OH-].[Na+]>CO.O1CCCC1>[CH:27]1([N:25]([CH2:24][C:22]2[CH:23]=[C:14]([C:13]#[C:12][C:9]3[CH:10]=[CH:11][C:6]([CH:4]([CH3:5])[C:3]([OH:34])=[O:2])=[CH:7][CH:8]=3)[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([CH3:30])([CH3:31])[CH2:18][C:17]3([CH3:33])[CH3:32])[CH3:26])[CH2:29][CH2:28]1
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C(=O)O)c1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
A solution of 2-(4-{8-[(cyclopropyl-methyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman-6-ylethynyl}-phenyl)-propionic acid methyl ester (Intermediate 14, 0.057 g, 0.12 mmol) in methanol (1 mL) and tetrahydrofuran (3 mL) was treated with a 1M solution of sodium hydroxide (0.3 mL, 0.3 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo to a residue that was washed with hexane, neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow solid (0.024 g, 45%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]2[CH:14]=[C:13](I)[CH:12]=[N:11]2)[CH:9]=1)[C:5]#[N:6].[NH:16]1[CH:20]=[CH:19][CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[N:16]1([C:13]2[CH:12]=[N:11][N:10]([C:8]3[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[CH:9]=3)[C:5]#[N:6])[CH:14]=2)[CH:20]=[CH:19][CH:18]=[N:17]1
Reactant: c1cn[nH]c1
Reactant: N#Cc1cc(F)cc(-n2cc(I)cn2)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1cc(F)cc(-n2cc(-n3cccn3)cn2)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a sealed tube containing dry, deoxygenated dioxane (1 mL) was added 3-fluoro-5-(4-iodo-1H-pyrazol-1-yl)benzonitrile (313 mg, 1.0 mmol), pyrazole (88 mg, 1.3 mmol), trans-diaminocyclohexane (24 μL, 0.2 mmol), potassium carbonate (304 mg, 2.2 mmol), and CuI (4 mg, 0.02 mmol). The reaction was capped and heated with stirring for 48 hr at 100° C. The resulting mixture was partitioned with EtOAc (10 mL) and H2O (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo on to a plug of silica gel, which was loaded on to a prepacked column and purified via automated flash chromatography utilizing a 5-35% EtOAc/Hexanes gradient to afford 3-(1′H-1,4′-bipyrazol-1′-yl)-5-fluorobenzonitrile as a white solid. 1H NMR (CDCl3, 500 MHz) δ 8.48 (s, 1H), 8.04 (s, 1H), 7.96 (m, 1H), 7.85-7.88 (m, 2H), 7.71 (d, 1H), 7.36 (m, 1H), 6.50 (m, 1H). MS (ESI) 254.15 (M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[O:12][C@@H:11]1[CH2:17][OH:18])([O-])=O>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:10]1[O:14][C:13]([CH3:15])([CH3:16])[O:12][C@@H:11]1[CH2:17][OH:18]
Reactant: CC1(C)O[C@H](c2ccccc2[N+](=O)[O-])[C@@H](CO)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC1(C)O[C@H](c2ccccc2N)[C@@H](CO)O1
Reaction time: 6 h
Yield: 60.8 %

Procedure:
To a stirred solution of ((4R,5R)-5-(2-nitrophenyl)-2,2-dimethyl-1.3-dioxolane-4-yl)methanol (Preparation example 46, 14 g) in EtOAc was added Pd(OH)2 (20 wt %, 2.8 g) under hydrogen gas (balloon). The mixture was stirred for 6 h then the resulting mixture was filtered through celite and concentrated under reduced pressure. The crude product was purified by SiO2 gel column chromatography to give title compound (7.5 g 65˜85%)
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([S:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)=[C:6]([Cl:20])[CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O>ClCCl>[C:1]([C:4]1[C:9]([O:10][CH3:11])=[C:8]2[C:7](=[C:6]([Cl:20])[CH:5]=1)[S:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]2=[O:17])([OH:3])=[O:2]
Reactant: COc1cc(SCC(C)(C)C(=O)O)c(Cl)cc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1c(C(=O)O)cc(Cl)c2c1C(=O)C(C)(C)CS2
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
19.9 Grams (62 mmol) of 3-(4-carboxy-2-chloro-5-methoxyphenylthio)pivalic acid was dissolved in 400 ml of dichloromethane, and while the reaction temperature was maintained below 5° C. with ice bath cooling, 16.9 ml (corresponding to 81 mmol of SO3) of 20 wt % fuming sulfuric acid was gradually added. The reaction mixture was stirred at the same temperature for 30 minutes, then the ice bath was removed and stirred for 1 hour. Ice water was added to the reaction mixture to wash an organic layer, and then the organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 15.6 g (yield 83%) of the titled compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:35][C:36]1[CH:46]=[CH:45][C:39]([CH2:40][NH:41][CH:42]2[CH2:44][CH2:43]2)=[C:38]([O:47][C@H:48]([CH2:50][CH:51]=[CH2:52])[CH3:49])[CH:37]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:41]([CH:42]4[CH2:44][CH2:43]4)[CH2:40][C:39]4[CH:45]=[CH:46][C:36]([CH3:35])=[CH:37][C:38]=4[O:47][C@H:48]([CH2:50][CH:51]=[CH2:52])[CH3:49])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1CNC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN(Cc4ccc(C)cc4O[C@@H](C)CC=C)C4CC4)nn23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (95 mg, 0.163 mmol) in acetonitrile (3 mL) at 0° C. was added (S)—N-(4-Methyl-2-(pent-4-en-2-yloxy)benzyl)cyclopropanamine (40 mg, 0.163 mmol) and Hunig's Base (0.028 mL, 0.163 mmol). It was stirred at 0° C. for 2 h and then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was then purify by 20% EtOAc/hexane to obtain (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((cyclopropyl(4-methyl-2-((S)-pent-4-en-2-yloxy)benzyl)amino)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.128 mmol, 79% yield) as an oil. LCMS (M+1)=702.5.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:11]3[NH:12][CH:13]=[CH:14][C:15](=O)[C:10]=3[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:25].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[Cl:25][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[O:17][C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]=12
Reactant: O=c1cc[nH]c2oc(-c3ccc(O)cc3)c(-c3ccccc3)c12
Reactant: ClC(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Oc1ccc(-c2oc3nccc(Cl)c3c2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 25-ml round bottom flask equipped with a reflux condenser fitted with a nitrogen inlet adapter was charged with 2-(4-hydroxy-phenyl)-3-phenyl-7H-furo[2,3-b]pyridin-4-one (5) (0.280 g, 0.923 mmol) and chloroform (9.0 mL). Oxalyl chloride (0.469 g, 0.32 mL, 3.69 mmol) and DMF (0.05 mL) were added and the mixture stirred at room temperature until the evolution of gas ceased (approx. 1 min). The mixture was heated at reflux for 5 h. The reaction mixture was concentrated to afford an orange brown solid which was purified via column chromatography on silica gel (eluting with 0-25% ethyl acetate-hexane) to afford 4-(4-chloro-3-phenyl-furo[2,3-b]pyridin-2-yl)-phenol 6 as an orange solid. MS (MH+) 322.0; Calculated 321 for C19H12ClNO2.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCCC1[O:19][CH2:20][CH2:21][O:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]>CO>[OH:19][CH2:20][CH2:21][O:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]
Reactant: O=C1c2ccccc2C(=O)N1OCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.56 g of p-toluenesulfonic acid monohydrate was added to a solution of 8.62 g of N-[2-(tetrahydropyran-2-yloxy)ethoxy]phthalimide [prepared as described in step (a) above] in 86 ml of methanol, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and then the resulting residue was dissolved in a mixture of ethyl acetate and water and neutralyzed with sodium hydrogen carbonate. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, giving the title compound as a crystalline powder. This was washed with diisopropyl ether to give 4.10 g of the pure compound, melting at 82°-85° C.