Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:19])[C:13]=2[CH2:15][N:16]([CH3:18])[CH3:17])[N:8]([CH3:20])[C:7]=1[CH2:21][CH2:22][CH3:23])=[O:5])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)C=NC[CH2:29]2>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2=[C:13]3[C:12](=[CH:11][CH:10]=[C:9]2[N:8]([CH3:20])[C:7]=1[CH2:21][CH2:22][CH3:23])[O:19][CH:17]1[N:16]([CH2:18][CH2:29][C:28]2[CH:27]=[C:26]([O:25][CH3:24])[CH:35]=[CH:34][C:33]=21)[CH2:15]3)=[O:5])[CH3:2]
Reactant: CCCc1c(C(=O)OCC)c2c(CN(C)C)c(O)ccc2n1C
Reactant: COc1ccc2c(c1)CCN=C2
Product: CCCc1c(C(=O)OCC)c2c3c(ccc2n1C)OC1c2ccc(OC)cc2CCN1C3
Yield: 7.7 %

Procedure:
By following the general procedure of Example 2 for the preparation of 9-methoxy-2-propyl-11,12-dihydro-3H,6αH,13H-6-oxa-3,12α-diaza-benzo[a]cyclopent[h]anthracene-1-carboxylic acid ethyl ester, 4-(dimethylamino-methyl)-5-hydroxy-1-methyl-2-propyl-1H-indole-3-carboxylic acid ethyl ester (2.1 g, 6.6 mmol) was reacted with 6-methoxy-3,4-dihydro-isoquinoline (1.005 g, 6.6 mmol) to give the desired product (0.22 g, 8%). MP 150-151° C. MS: 435.2 (M+1+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]4[CH2:19][CH2:20][C:21]5[NH:22][C:23](=[O:26])[CH:24]=[CH:25][C:16]([C:17]=54)=[CH:15][N:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.N.[CH:28](Cl)(Cl)Cl.[K+].[Br-]>>[CH3:28][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]4[CH2:19][CH2:20][C:21]5[NH:22][C:23](=[O:26])[CH:24]=[CH:25][C:16]([C:17]=54)=[CH:15][N:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: ClC(Cl)Cl
Reactant: O=C1C=CC2=CN=C(c3ccc(C4CCNCC4)cc3)N3CCC(=C23)N1
Agent: N
Agent: [Br-]
Agent: [K+]
Product: CN1CCC(c2ccc(C3=NC=C4C=CC(=O)NC5=C4N3CC5)cc2)CC1

Procedure:
The product was prepared from 1-(4-piperidin-4-yl-phenyl)-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (Example 137) following the procedure for Example 132 a white solid (77%): mp >240° C. (dec); Rf=0.21 (10% methanolic ammonia/CHCl3); IR (KBr) 1662, 1473, 1379, 1304 cm−1; 1H NMR (DMSO-d6) δ 1.69-1.81 (m, 4H), 2.00-2.07 (m, 2H), 2.23 (s, 3H), 2.53-2.58 (m, 1H), 2.89-2.93 (m, 2H), 3.51-3.52 (m, 2H), 4.45-4.47 (m, 2H), 7.34 (t, 1H, J=7.8 Hz), 7.45 (d, 2H, J=8.2 Hz), 7.79 (d, 2H, J=8.3 Hz), 7.84-7.90 (m, 2H), 8.44 (t, 1H, J=5.6 Hz). HRMS calcd for C22H24N4O 360.1950 (M+), found 360.1944. Anal. (C22H24N4O.0.25H2O) C, H, N.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH:25]=2)[C:23]#[N:24])[CH:3]=1.[NH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:25]=3)[C:23]#[N:24])[CH:3]=[C:2]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(-c2cncc(C#N)c2)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cncc(C#N)c2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
55 mg of (S)-5-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}nicotinonitrile, 16 mg of 2-aminopyrazine, 15 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 21 mg of sodium t-butoxide and 8 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 21 mg of the objective compound as white powder.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2([C:23](OC(C)(C)C)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)(O)=[O:2].O.[OH:31][N:32]1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:48]1([CH3:58])[C:49]([C:54]([NH:56][NH2:57])=O)=[CH:50][CH:51]=[CH:52][CH:53]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[OH:31][NH:32][C:23]([C:17]1([S:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][C:1]3[O:2][C:54]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=4[CH3:58])=[N:56][N:57]=3)=[CH:13][CH:12]=2)(=[O:16])=[O:15])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:24]
Reactant: Cc1ccccc1C(=O)NN
Reactant: CC(C)(C)OC(=O)C1(S(=O)(=O)c2ccc(OCCCC(=O)O)cc2)CCOCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccccc1-c1nnc(CCCOc2ccc(S(=O)(=O)C3(C(=O)NO)CCOCC3)cc2)o1
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Part A. In dry equipment under nitrogen, 4-[[4-(3-carboxypropoxy)phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylic acid, 1,1-dimethylethyl ester (2.14 g, 5.0 mmol, prepared as in Example 7) was dissolved in dry N,N-dimethylformamide (10 mL), and the remaining reagents were added to the solution in the following order: 1-hydroxybenzotriazole hydrate (945 mg, 7.0 mmol), triethylamine (0.84 mL, 6.0 mmol), o-toluic hydrazide (901 mg, 6.0 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g, 7.5 mmol). After 2 hr at 35° C., the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate; washed with water, saturated sodium bicarbonate solution, and brine; dried over sodium sulfate; filtered; and concentrated in vacuo. Purification by flash column chromatography using ethyl acetate/hexanes provided 2.32 g (83%) of the desired product as a white foam. ESMS m/z=583 [M+Na]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]2[CH2:17][CH:12]1[CH2:13][C:14]2([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]([CH2:29][C:30]([O:32]CC)=[O:31])[C:22]2=[O:35])O)=[O:10])C1C=CC=CC=1.I.C(Cl)(OC[CH:41]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]2[C:42]1=[CH:43][CH:44]=[CH:45][CH:46]=2)=O>CC(O)=O>[CH:43]1[C:42]2[CH:41]([CH2:1][O:8][C:9]([N:11]3[CH2:16][CH:15]4[CH2:17][CH:12]3[CH2:13][CH:14]4[C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][N:23]([CH2:29][C:30]([OH:32])=[O:31])[C:22]4=[O:35])=[O:10])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47]=2[CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CCOC(=O)Cn1cnc2ccc(C3(O)CC4CC3CN4C(=O)OCc3ccccc3)cc2c1=O
Agent: I
Solvent: CC(=O)O
Product: O=C(O)Cn1cnc2ccc(C3CC4CC3CN4C(=O)OCC3c4ccccc4-c4ccccc43)cc2c1=O
Temperature: 120 °C
Reaction time: 5 h
Yield: 42 %

Procedure:
To a mixture of 13 (22.4 g, 47 mmol) in HOAc (448 mL) was added HI (268 mL). The mixture was heated to reflux at 120° C. overnight. The reaction mixture was evaporated and its pH was adjusted to 6-7 with potassium carbonate and NaHCO3. Then 50 mL of tetrahydrofuran was added. To the mixture was added FmocCl (15.68 g, 61 mmol) and stirred at room temperature for 5 h. Then the reaction mixture was extracted with ethyl acetate and washed with water 3 times. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. Purification by chromatography (eluant:methylene chloride to methylene chloride/MeOH/HAc 8/1/0.1) gave 10.3 g of crude 5-(3-carboxymethyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid 9H-fluoren-9-ylmethyl ester which was further purified by preparative HPLC to give 2.7 g of pure 5-(3-carboxymethyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid 9H-fluoren-9-ylmethyl ester (11% yield in 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:29][C:26]1[CH:25]=[CH:24][C:23]([C@H:22]2[C:15]3=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]3[CH2:19][CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1cccc(Oc2ccc([C@@H]3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
A mixture of (3-methoxyphenyl)boronic acid (813 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL), cesium carbonate (581 mg), diacetoxycopper (648 mg), and powdered 4A MS (5.00 g) in MeCN (18 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column is chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc to give the title compound (80.0 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1Br.[C:8](=[O:10])=[O:9].CC(C)=O.C([Li])CCC.C(=O)=O>C(OCC)C>[Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:8]([OH:10])=[O:9]
Reactant: Clc1sccc1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C(O)c1ccsc1Cl
Temperature: 25 °C
Yield: 90 %

Procedure:
To a round bottomed flask were added 2-chloro-3-bromothiophene (26.2 g, 132.7 mmole) along with diethyl ether (390 mL). The reaction was cooled to -78° C. (dry ice/acetone) and 1.6M n-butyllithium (87.0 mL, 139.0 mmole) was added dropwise. The reaction was stirred for 1.5 hours after which an excess of CO2 (~25.0 g) was added all at once. The reaction was warmed to room temperature and poured onto ice/water. The mixture was extracted with 10% sodium carbonate solution and the basic aqueous layer was washed with methylene chloride. The basic solution was then acidified to a pH 3.0 and extracted with diethyl ether. The organic layer was washed with water, brine, and dried (MgSO4). Solvent removal yielded 19.32 g of an off-white solid (90%) which was used as is.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccccc1C(O)CCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC/C=C/c1ccccc1CCCCCCCCC

Procedure:
A mixture of 14.4 g of 1-(2-nonylphenyl)-1-hexanol, 2 g of toluene-4-sulphonic acid monohydrate and 250 ml of toluene is heated under reflux for 3 hours using a water separator. After cooling, the reaction mixture is washed twice with 10% strength (w/v) sodium bicarbonate solution and twice with water. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo, and the residue is purified by chromatography on silica gel using hexane as eluant. The desired 1-(2-nonylphenyl)-transhexene is obtained in the form of a pale yellow oil. IR (CH2Cl2): 2960, 2930, 2855, 1465, 970 cm-1.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9].S(Cl)([Cl:18])=O>N1C=CC=CC=1.C(Cl)Cl>[Cl:18][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(C)Oc1cccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(C)Oc1cccc(CCl)c1
Yield: 88.8 %

Procedure:
By the method of Example 1, Step J, 1.98 g (0.0095 mole) of methyl 2-(3-hydroxymethylphenoxy)propionate and 1.24 g (0.0105 mole) of thionyl chloride were reacted in the presence of five drops of pyridine in 40 mL of methylene chloride, yielding 1.93 g of methyl 2-(3-chloromethylphenoxy)propionate as a yellow liquid. The NMR and IR spectra were consistent With the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:14]1[N:15]=[CH:16][C:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])=[N:18][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C(OCC)C.O.CS(C)=O>[CH3:23][N:22]([CH3:24])[C:20]([C:17]1[N:18]=[CH:19][C:14]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:15][CH:16]=1)=[O:21]
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(O)cc(Oc2cnc(C(=O)N(C)C)cn2)c1
Temperature: 50 °C

Procedure:
To methyl 3,5-dihydroxybenzoate (CAS no. 2150-44-9) (85 g, 0.49 mol) was added 5-chloro-N,N-dimethyl-pyrazine-2-carboxamide (88.9 g, 0.48 mol), DMSO (1000 mL,) and cesium carbonate (418 g, 1.2 mol) and the mixture was heated to 50° C. for 3 hours. Water (1577 mL,) was charged followed by diethyl ether (540 mL). To the aqueous layer was charged 5M hydrochloric acid solution (395 mL, 1.97 mol) and the resulting white solid was filtered washed with water (2×311 mL) and dried under vacuum at 40° C. over P2O5 overnight to give the desired compound (143 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1C1C=CC=CC=1.O1C=CC=C1C1C=C2C(=CC=1)C(=O)NC(=O)C2=COC.NCC1C=CC([I:59])=C(O)C=1>>[OH:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[I:59])[CH2:8][NH:9][CH:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[C:14](=[O:22])[NH:13][C:12]1=[O:23]
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Reactant: NCc1ccc(I)c(O)c1
Agent: COC=C1C(=O)NC(=O)c2ccc(-c3ccco3)cc21
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(I)c(O)c1
Yield: 80 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-Furan-2-yl-4-methoxymethylene-4H-isoquinoline-1,3-dione (60 mg, 0.22 mmol) and 5-Aminomethyl-2-iodo-phenol (58 mg, 0.23 mmol) in 80% yield: MS (ESI): 485.1 (M−1)−1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11]1[C:18](Cl)=[N:17][C:15](Cl)=[N:14][C:12]=1[Cl:13].[C:20](=[O:23])([O-])[O-:21].[Na+].[Na+]>CC(C)=O.O>[Cl:13][C:12]1[N:11]=[C:18]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[N:17]=[C:15]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:20]([OH:21])=[O:23])=[CH:4][CH:3]=2)[N:14]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C([O-])[O-]
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(Nc2nc(Cl)nc(Nc3ccc(C(=O)O)cc3)n2)cc1
Temperature: 25 °C
Yield: 101.9 %

Procedure:
To 350 grams of 4-aminobenzoic acid and 7437.5 grams of water at 11° C. was added a solution of 157.1 grams of cyanuric chloride in 739.93 grams of acetone and a solution of 135.2 grams of sodium carbonate in 993.5 grams of water simultaneously dropwise at a rate such that the temperature was maintained below 15° C. Following the addition the batch was allowed to mix for one hour at 15° C. and then warmed to room temperature. The solid was collected, washed with water and acetone and dried to give 335 grams of 4,4′-[(6-chloro-1,3,5-triazine-2,4-diyl)diimino]bis-benzoic acid (1) as a white/tan solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:35][C:31]1[CH:30]=[C:29]([C:5]2[C:4]([C:1]([NH2:2])=[O:3])=[C:8]3[CH2:9][N:10]([C:13]([NH:15][CH:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)=[O:14])[CH2:11][CH2:12][N:7]3[N:6]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)N2CCn3nc(-c4cccc(F)c4)c(C(N)=O)c3C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(-c2cccc(F)c2)nn2c1CN(C(=O)NC1CCNCC1)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To a solution of Intermediate 97A (300 mg, 0.617 mmol) in DCM (3 mL) was added TFA (0.238 mL, 3.08 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and the resultant residue was basified to pH=8.0 with 10% NaHCO3 solution. The aqueous layer was extracted with DCM (3×5 mL) and the combined organic layer was washed with water (2×5 mL), brine, dried over Na2SO4, filtered and concentrated to afford Intermediate 97B (200 mg, 80%) as white solid. MS(ES): m/z=387 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (bs, 1H), 7.46 (m, 3H), 7.32 (bs, 1H), 7.21 (m, 1H), 7.11 (bs, 1H), 6.86 (d, J=7.03 Hz, 1H), 4.74 (s, 2H), 4.15 (t, J=5.27 Hz, 2H), 3.86 (t, J=5.27 Hz, 2H), 3.72 (m, 1H), 3.27 (s, 2H), 2.96 (m, 2H), 1.93 (m, 2H), 1.54 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[OH:19][CH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27](O)=[O:28])[CH2:22][CH2:21]1.COC1C2N=C(NC(=O)CC3CCOCC3)SC=2C(C2CCOCC2)=CC=1>>[OH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][C:27]([NH:12][C:10]2[S:11][C:7]3[C:6]([CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:28])[CH2:22][CH2:21]1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)CC1CCC(O)CC1
Agent: COc1ccc(C2CCOCC2)c2sc(NC(=O)CC3CCOCC3)nc12
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@H](O)CC3)nc12

Procedure:
Using 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine and (4-hydroxy-cyclohexyl)-acetic acid, the title compound was prepared in the same manner as described for N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-(tetrahydro-pyran-4-yl)-acetamide and obtained as white crystals (25% yield). Mp 120-145° C., MS: m/e=405(M+H+).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)=[CH:27][CH:26]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23])[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1NC(=O)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: N#Cc1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.5 %

Procedure:
To a solution of N-(2-(3-cyano-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide (42.7 mg, 0.10 mmol) in DCM (3 mL) was added 4-fluorophenylboronic acid (17 mg, 0.12 mmol), TEA (21 mg, 0.2 mmol) and Cu(OAc)2 (22 mg, 0.12 mmol). After stirring at RT for 16 hr, the mixture was purified by Pre-TLC (DCM/CH3OH=20/1) to afford 30 mg (57%) of N-(2-(3-cyano-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.90-7.77 (m, 3H), 7.52-7.37 (m, 3H), 7.34-7.27 (m, 2H), 7.22-7.14 (m, 2H), 7.10 (d, J=8.8 Hz, 2H), 6.80 (d, J=6.4 Hz, 1H), 5.80-5.75 (m, 1H), 3.37-3.28 (m, 1H), 3.09-2.95 (m, 1H), 2.50-2.37 (m, 1H), 2.10-1.95 (m, 1H). MS (ESI) m/e [M+1]+ 521.8.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[C:29]([CH2:30][CH3:31])=[C:28]([CH3:32])[C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:6]([CH3:33])[C:5]=1[CH2:34][CH3:35].[CH2:36]([O:38][C:39](=[O:50])[CH:40]=[C:41]([CH3:49])[CH:42]=[CH:43][CH:44]=[C:45]([CH:47]=O)[CH3:46])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:50])[CH:40]=[C:41]([CH3:49])[CH:42]=[CH:43][CH:44]=[C:45]([CH3:47])[CH:46]=[CH:8][C:7]1[C:6]([CH3:33])=[C:5]([CH2:34][CH3:35])[C:4]([O:3][CH3:2])=[C:29]([CH2:30][CH3:31])[C:28]=1[CH3:32])[CH3:37]
Reactant: CCc1c(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c(CC)c1OC
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)c(CC)c(OC)c(CC)c1C

Procedure:
4-methoxy-3,5-diethyl-2,6-dimethyl-benzyl-triphenylphosphonium chloride is condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to produce the 9-(4-methoxy-3,5-diethyl-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester which is converted by the procedure of Example 7 to 9-(4-methoxy-3,5-diethyl-2,6-dimethyl-phenyl)-acid, m.p.: 153°-154° C.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[N:8]1([C:14]2([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][NH:16][CH2:15]2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(N(CC)CC)C.CN(C)CCN>ClCCl>[N:8]1([C:14]2([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:17][N:16]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH2:15]2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC1(N2CCOCC2)CNC1
Agent: CN(C)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N1CC(CNC(=O)OC(C)(C)C)(N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Propane-1-sulfonyl chloride (0.44 ml, 3.9 mmol) was added to tert-butyl [(3-morpholin-4-ylazetidin-3-yl)methyl]carbamate (0.71 g, 2.6 mmol) and triethylamine (0.91 g, 6.5 mmol) in dichloromethane (9 ml) at 0° C. The reaction was then stirred at room temperature for 30 mins before quenching with N,N-dimethylethylenediamine (0.5 eq). The resulting mixture was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness to give crude tert-butyl {[3-morpholin-4-yl-1-(propylsulfonyl)azetidin-3-yl]methyl}carbamate which was used without further purification m/z (M++H) 378.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f22) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: Cc1cccc(C(=O)O)c1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(C)c1F
Reaction time: 8 h
Yield: 83 %

Procedure:
To a stirred solution of 2-fluoro-3-methylbenzoic acid (4.0 g, 26.0 mmol) in anhydrous methanol (52 mL) at 0° C. was added thionyl chloride (2.8 mL, 39.0 mmol) dropwise and the reaction mixture was stirred overnight at reflux. The mixture was diluted with methanol and concentrated under reduced pressure to remove the excess thionyl chloride. The residue was then dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 2-fluoro-3-methylbenzoate (3.6 g, 83%) as a clear oil that was used in the next step without further purification: 1H NMR (500 MHz, CDCl3) δ 7.75-7.72 (m, 1H), 7.38-7.35 (m, 1H), 7.26-7.06 (m, 1H), 3.91 (s, 3H), 2.31 (s, 3H).