Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]1[C:15](=[O:16])[CH2:14][CH:13]2[CH2:17][CH2:18][CH2:19][CH:12]12.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH2:30]Br>C1COCC1>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH2:30][CH:14]1[C:15](=[O:16])[O:11][CH:12]2[CH2:19][CH2:18][CH2:17][CH:13]12
Reactant: BrCc1ccc2ccccc2c1
Reactant: O=C1CC2CCCC2O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OC2CCCC2C1Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon, 8.7 ml of a 1 molar solution of lithium bis-(trimethylsilyl)-amide in THF are added dropwise to a solution, cooled to −78° C., of 1 g (7.9 mmol) of hexahydro-cyclopenta[b]furan-2-one in 20 ml of THF such that the temp. of the mixture does not exceed −65° C. After the addition has ended, stirring is continued at −78° C. for 10 min, and 1.93 g (8.7 mmol) of naphth-2-ylmethyl bromide are then added in one portion. Immediately afterwards, the cooling bath is removed and the mixture is allowed to warm to room temp. After 16 h of stirring at room temp., the mixture is taken up in water/diethyl ether and the aqueous phase is extracted twice with diethyl ether. The combined organic phases are dried over sodium sulphate and then concentrated. The residue is chromatographed over silica gel (mobile phase: dichloromethane); Yield: 1.2 g, colourless oil, diastereomer mixture: 87:13 (Example 1) 1H-NMR (200 MHz; [d6]-DMSO): δ[ppm]=1.2-1.9 (br m,7H), 2.6 (m,1H), 2.87 (dd, 1H); 2.93 (dd,1H), 4.72/4.75 (m;1H), 7.48-7.55 (m;3H), 7.76 (s;1H), 7.81-7.95 (m;3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[N:26][C:21]=1[NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[O:10])[CH2:5][CH2:4]1
Reactant: Clc1ncccn1
Reactant: Cc1ccc(COC(=O)N2CCC(CN)CC2)cc1
Product: Cc1ccc(COC(=O)N2CCC(CNc3ncccn3)CC2)cc1

Procedure:
The title compound was prepared as described in EXAMPLE 13, except using 4-methylbenzyl 4-(aminomethyl)-1-piperidinecarboxylate (300 mg, 1.14 mmol), 2-chloropyrimidine (131 mg, 1.14 mmol) as starting materials gave the title compound as a yellow oil.
Reaction SMILES: ClC(OC(Cl)C)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([CH:21]3[CH2:26][CH2:25][N:24](C)[CH2:23][CH2:22]3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1.CO>ClCCCl.C(OCC)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CN1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCOCC
Solvent: ClCCCl
Solvent: CO
Product: Clc1ccc(-c2cnc(C3CCNCC3)nc2)cc1
Reaction time: 20 h
Yield: 76.1 %

Procedure:
1-Chloroethyl chloroformate (0.50 ml) was added to a solution of 5-(4-chlorophenyl)-2-(1-methylpiperidin-4-yl)pyrimidine (0.170 g) in anhydrous 1,2-dichloroethane (10 ml) and the mixture heated to reflux, under a calcium chloride guard tube, for 20 h. The reaction was then cooled, treated with methanol (1.0 ml), and returned to reflux for a further hour. After cooling, the reaction was diluted with diethyl ether (20 ml) and extracted with water (20 ml), 0.2 M hydrochloric acid (10 ml) then 1% citric acid (50 ml). The combined aqueous extracts were back-extracted with diethyl ether (10 ml), basified to pH 13 with 46% aqueous sodium hydroxide and extracted with ethyl acetate (20 ml, then 2×10 ml). The combined ethyl acetate extracts were washed with water (10 ml), saturated brine (20 ml), dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a white solid (0.123 g, 76%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:27])[NH:20][C:21]([CH3:26])=[CH:22][C:23]=2[CH2:24][CH3:25])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[Na].[CH3:29][S:30]([OH:32])=[O:31]>>[CH2:24]([C:23]1[CH:22]=[C:21]([CH3:26])[NH:20][C:19](=[O:27])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:3]=1)=[O:15])[CH3:25]
Reactant: CS(=O)O
Reactant: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Agent: [Na]
Product: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(S(C)(=O)=O)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared from 6-bromo-N-[(4-ethyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (70 mg, 0.162 mmol) and the sodium salt of methanesulfinic acid (33.5 mg, 0.325 mmol), in the same manner as described for example 91. The product was collected as a white solid (21 mg) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.17 (m, 3H), 1.47-1.56 (m, 6H), 2.15 (s, 3H), 2.58 (q, J=7.58 Hz, 2H), 3.03 (s, 3H), 4.33-4.47 (m, 2H), 5.17-5.30 (m, 1H), 5.94 (s, 1H), 8.01 (d, J=1.26 Hz, 1H), 8.45 (m, 1H), 8.53 (s, 1H), 8.78 (t, J=4.93 Hz, 1H); LCMS: (M+H)+=431.1
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][C:10]1[CH:40]=[C:39]([F:41])[C:13]([C:14]([NH:16][C@@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29](=[O:38])[N:30]([CH3:37])[C:31](=[O:36])[N:32]([CH3:35])[C:33]=3[CH3:34])=[CH:24][CH:23]=2)[C:18]([OH:20])=[O:19])=[O:15])=[C:12]([F:42])[CH:11]=1.O=C1CCC(=O)N1[O:50][C:51](=O)[CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][NH:66][C:67](=[O:77])[CH2:68][CH2:69][N:70]1[C:74](=[O:75])[CH:73]=[CH:72][C:71]1=[O:76].CCN(C(C)C)C(C)C>>[O:76]=[C:71]1[CH:72]=[CH:73][C:74](=[O:75])[N:70]1[CH2:69][CH2:68][C:67]([NH:66][CH2:65][CH2:64][O:63][CH2:62][CH2:61][O:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][C:51]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([F:42])[C:13]([C:14]([NH:16][C@@H:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29](=[O:38])[N:30]([CH3:37])[C:31](=[O:36])[N:32]([CH3:35])[C:33]=3[CH3:34])=[CH:26][CH:27]=2)[C:18]([OH:20])=[O:19])=[O:15])=[C:39]([F:41])[CH:40]=1)=[O:50])=[O:77]
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CN)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CNC(=O)CCOCCOCCOCCOCCNC(=O)CCN4C(=O)C=CC4=O)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-(4-aminomethyl-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid TFA salt (120 mg, 0.2 mmol), 3-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (103 mg, 0.2 mmol), and DIPEA (129 mg, 174 uL, 1.0 mmol), and after HPLC purification, resulted in a white solid (75 mg, 43%). ES(+)-HRMS m/e calcd. for C42H50F2N6O13 (M+Na)+ 907.3296, obsd. 907.3296.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][C:21](=[N:35][NH:36][C:37]([NH2:39])=[O:38])[CH2:22][C@H:23]([NH:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH2:29])[CH:24]=[O:25])([CH3:19])([CH3:18])[CH3:17].O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NC(N)CC(C)C)C>CN1CCCC1=O.C(Cl)Cl>[C:16]([O:20][C:21](=[N:35][NH:36][C:37]([NH2:39])=[O:38])[CH2:22][C@H:23]([NH:26][C:27](=[O:34])[C@H:28]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:29][C:13](=[O:15])[CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH:24]=[O:25])([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Reactant: O=C(O)COc1cccc2ccccc12
Agent: CCN=C=NC(N)CC(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)COc1cccc2ccccc12)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
To a solution of (1-naphthyloxy)acetic acid (0.150 g, 0.74 mmol) and (3S)-3-(leucinyl)amino-4-oxobutanoic acid tert-butyl ester semicarbazone (0.360 g, ca 0.83 mmol) in N-methylpyrrolidone(2.0 mL)-CH2Cl2(2.0 mL) at 0° C. (ice bath) under nitrogen was added hydroxybenzotriazole hydrate (0.130 g) followed by 1-ethyl-3-(3′,3′-dimethyl-1′-aminopropyl)carbodiimide hydrochloride (0.195 g, 1.02 mmol). After stirring at 0° C. for 1 hrs and at room temperature for 5 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO4, saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography eluting with MeOH-CH2Cl2 (2:100 then 5:100) to give the title compound (0.366 g, 94%) as a colorless foam. TLC(MeOH-CH2Cl2; 5:95) Rf=0.20.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]2[C:7]([CH3:18])([CH3:17])[N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:3]=12.C(N(CC)C(C)C)(C)C.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[N:6]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:5]=[C:4]2[C:7]([CH3:18])([CH3:17])[N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:3]=12
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1Cc2c(n[nH]c2N)C1(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc2c(c1N)CN(C(=O)OC(C)(C)C)C2(C)C
Yield: 38 %

Procedure:
15 g of tert-Butyl 3-amino-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (59.4 mmol) were dissolved in anhydrous THF (150 ml) and treated, at 0° C. under Ar atmosphere, first with N,N-diisopropylethylamine (50 ml) and then with ClCO2Et (4.65 ml, 1 eq.) dropwise. 90 minutes later, the solvent was diluted with EtOAc (1 l), washed with water and then with brine, dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography (hexane/EtOAc 2/8) to afford 7.3 g of 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate as the major compound in 38% yield, together with 5.7 g of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate in 30% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=3)[N:15]=[C:14]2[CH:29]2[CH2:34][CH2:33][N:32]([C:35]3[C:40]([C:41]#[N:42])=[C:39]([NH2:43])[N:38]=[CH:37][N:36]=3)[CH2:31][CH2:30]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:44]O>CS(C)=O>[NH2:43][C:39]1[N:38]=[CH:37][N:36]=[C:35]([N:32]2[CH2:31][CH2:30][CH:29]([C:14]3[N:13]([CH:10]4[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]4)[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=4)[N:15]=3)[CH2:34][CH2:33]2)[C:40]=1[C:41](=[O:44])[NH2:42]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(c3ncnc(N)c3C#N)CC2)C1
Reactant: OO
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCN(c3ncnc(N)c3C(N)=O)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A reaction mixture of 3-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (100.00 mg; 0.17 mmol; 1.00 eq.) and 2.0N NaOHaq (0.83 ml; 1.66 mmol; 10.00 eq.), in DMSO 8 ml was stirred at RT for 5 mins, added H2O2 (0.16 ml; 1.66 mmol; 10.00 eq.) stirred at RT for 2 hr. Purified the product by HPLC (basic), collected title compound 45 mg, yield 43%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][C:14]=1[NH2:22].[SH:23][C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1>>[CH3:29][N:25]1[CH:26]=[CH:27][N:28]=[C:24]1[S:23][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:22][C:14]1[S:15][C:16]2[C:21]([N:13]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: Nc1nc2cccnc2s1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Cn1ccnc1S
Product: Cn1ccnc1Sc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1

Procedure:
The compound of Example 9 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, thiazolo[5,4-b]pyridin-2-yl-amine and 2-mercapto-1-methyl-imidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl.[N:11]([O-])=O.[Na+].[Cl:15][CH2:16][S:17]([CH2:20]C(=O)C)(=[O:19])=[O:18].C([O-])(=O)C.[Na+]>O.CC(C)=O>[Cl:15]/[C:16](=[N:11]\[NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)/[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: O=N[O-]
Reactant: CC(=O)CS(=O)(=O)CCl
Reactant: COc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(N/N=C(\Cl)S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 574.2 %

Procedure:
To a solution of p-anisidine (4.39 g, 3.6 mmol) in con. HCl (9.2 mL) and water (20 mL) at 0° C. was slowly added sodium nitrite (2.58 g, 3.7 mmol) in water (20 mL). The reaction mixture was stirred at 0° C. for 0.5 h. The above mixture was poured into a mixture of 3-chloromethanesulphonyl acetone (Grossert, J S, et. al., Can J. Chem. 1984, 62, 798)(6.1 g, 3.5 mmol), acetone (50 mL), sodium acetate (6.7 g, 8.2 mmol), and water (100 mL). The resulting mixture was stirred for 4 h at rt. The precipitate was filtered-off and dried to afford the hydrazone as a red solid (5.28 g, 57%); 1H NMR (CDCl3) δ: 8.05 (s, 1H), 7.12 (d, 2H), 6.91 (d, 2H), 3.80 (s, 3H), 3.23 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:28])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[CH:20]=2)[C:16]=1Cl)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[C:33]([CH3:40])=[C:34]2[C:39]=1[O:38][CH2:37][CH2:36][CH2:35]2.C([O-])([O-])=O.[K+].[K+]>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.CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:28])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[CH:20]=2)[C:16]=1[C:32]1[C:33]([CH3:40])=[C:34]2[C:39](=[C:30]([F:29])[CH:31]=1)[O:38][CH2:37][CH2:36][CH2:35]2)[C:7]([O:9][CH3:10])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
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: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 125 °C
Yield: 37.1 %

Procedure:
To a 2-5 ml microwave tube was added (S)-methyl 2-(tert-butoxy)-2-(7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (420 mg, 0.995 mmol), tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.099 mmol), 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (320 mg, 1.094 mmol), DMF (4 mL), followed by 2M K2CO3 solution (400 μl). The reaction mixture was heated in a microwave reactor at 125° C. for 45 min. The reaction mixture was filtered and the filtrate was purified by silica gel chromatography to afford (204 mg, 37.2%) of the title compound. Enantiomeric Excess was determined by Chiral SFC method: Chiralpak AD-H analytical column, 4.6×250 mm, 5 μm. Mobile Phase: 15% MeOH in CO2. Temp: 35° C. Flow rate: 2.0 mL/min. for 10 min. UV monitored @ 266 nm. Injection: 5 uL of ˜2.0 mg/mL solution in 50:50 MeOH:CHCl3. The enantiomeric Excess is 93.0%. 1H NMR (500 MHz, CHLOROFORM-d) δ 7.83-7.78 (m, 1H), 7.69 (dt, J=6.7, 1.8 Hz, 1H), 7.35-7.28 (m, 2H), 6.87 (d, J=10.7 Hz, 1H), 6.84 (s, 1H), 5.00 (s, 1H), 4.48-4.26 (m, 2H), 3.64 (s, 3H), 2.85-2.67 (m, 5H), 2.30-2.13 (m, 2H), 1.84 (s, 3H), 1.16 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)[CH3:2].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:18]1[C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]1=[O:19])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)CCCCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCN1C(=O)c2ccccc2C1=O
Yield: 79.4 %

Procedure:
A mixture of 26.4 g (0.1 mole) of ethyl-8-bromooctanoate (95%, Pfaltz and Bauer) and 19.6 g (0.1 mole) of potassium phthalimide (98%, Aldrich) in 250 mL of dimethylformamide was stirred and heated at reflux for 4 hr. The solvent was evaporated under reduced pressure and the viscous residue was partitioned between ethyl ether and water (400 mL each). The aqueous layer was further extracted with two 200 mL of ethyl ether. The combined ether extracts were washed with 200 mL of water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the viscous, oily residue was triturated with ethyl ether-petroleum ether (30°-60° C.) and the resulting solid was collected by filtration. The filtrate was evaporated under reduced pressure to give 25.2 g (79%) of crude title compound as a viscous oil. A 2.0 g sample of this oil was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrepPak® 500 silica; ethyl acetate-hexanes, 1:20; flow rate: 200 mL/min.). Fractions containing title compound were combined and the solvents were evaporated under reduced pressure to give 1.9 g (95% recovery) of clear liquid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].Br[C:13]1[C:14]2[C:19]([CH:20]=[C:21]3[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]3)=[CH:18][CH:17]=[CH:16][CH:15]=2.C([O-])([O-])=O.[K+].[K+].C(O)CO>C(O)(CC)(C)C.[Cu]I.ClCCl>[CH:15]1[C:14]2[C:19](=[CH:20][C:21]3[C:26]([C:13]=2[S:11][C:2]2[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][CH:16]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: Sc1ccc2ccccc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: ClCCl
Solvent: CCC(C)(C)O
Product: c1ccc2cc(Sc3c4ccccc4cc4ccccc34)ccc2c1
Yield: 50.6 %

Procedure:
A mixture of 2-naphthalenethiol (15.5 g, 0.097 mol), 9-bromoanthracene (25.0 g, 0.0.097 mol), CuI (19.1 g, 0.1 mol), K2CO3 (15.0 g, 0.11 mol), KI (16.6 g, 0.1 mol) and ethylene glycol (10 mL) in tert-amyl alcohol (500 mL) were refluxed for 48 h under N2. After cooling, dichloromethane was added and the mixture washed with 2N NaOH and water, and filtered through an alumina plug. Solvent was removed by rotary evaporation under vacuum and the residue purified by column chromatography (silica/hexanes) to yield 16.5 g (50.5%) of the sulfide. 1H NMR (CDCl3) δ 7.13 (dd, J=8.7, 1.85 Hz, 1H) 7.28-7.35 (m, 3H), 7.43-7.47 (m, 1H), 7.49-7.56 (m, 4H), 7.58 (d, J=8.7 Hz, 1H), 7.66-7.70 (m, 1H), 8.06-8.10 (m, 2H), 8.64 (s, 1H), 8.84-8.89 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:20](O)=[O:21])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:27][O:26][N:25]([CH3:24])[C:20]([C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[CH:8][C:7]=2[CH:19]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:21]
Reactant: CNOC
Reactant: COc1ccc(-c2cc3cc(OC)cc(C(=O)O)c3o2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(OC)cc(C(=O)N(C)OC)c3o2)cc1
Yield: 72 %

Procedure:
A solution of 23 (1.7 g, 5.7 mmol), N,O Dimethylhydroxyamine HCl (1.7 g, 17.1 mmol), DMAP (2.1 g, 17.1 mmol), and EDCl (1.9 g, 10 mmol) in DMF (30 ml) was stirred at rt for 1 hr. The reaction was then poured into 2 NHCl and extracted with EtOAc which was dried over MgSO4, concentrated, and the product was purified by column chromatography on silica gel (30% Et OAc/Hex) to give 121 as a solid (1.4 g, 74%); Mp=109–111° C.; 1H NMR (CDCl3) δ 7.77 (d, 2 H, J=8.7 Hz), 7.09 (d, 1 H, J=2.4 Hz), 6.99–6.95 (m, 3 H), 6.84 (s, 1 H), 3.86 (s, 6 H), 3.69 (s, 3 H), 3.40 (s, 3 H); MS 342 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39](Br)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: CC(C)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) (402 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (310 mg, 53%). MS (ISN) 582.0 [(M−H)−]; mp 226-227° C.
Reaction SMILES: C([Cl:4])(=O)C.C(OC([N:12]1[CH2:36][CH2:35][C:15]2([CH2:18][N:17]([C@H:19]3[C:27]4[C:22](=[CH:23][C:24]([C:28]5[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)[CH2:16]2)[CH2:14][CH2:13]1)=O)(C)(C)C>CO>[ClH:4].[ClH:4].[CH3:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[CH:19]([N:17]2[CH2:18][C:15]4([CH2:35][CH2:36][NH:12][CH2:13][CH2:14]4)[CH2:16]2)[CH2:20][CH2:21]3)[CH:33]=1
Reactant: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)ncn1
Reactant: CC(=O)Cl
Solvent: CO
Product: Cc1cc(-c2ccc3c(c2)CCC3N2CC3(CCNCC3)C2)ncn1
Product: Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 102.4 %

Procedure:
A flask containing methanol (100 mL) was cooled to 0° C. The solution was then charged dropwise with acetyl chloride (16.38 mL, 230.11 mmol) over 1 h maintaining a temperature of 10° C. The resulting mixture was charged with 2-[(R)-5-(6-methylpyrimidin-4-yl)-indan-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3-1f, 10.0 g, 23.01 mmol) in methanol (50 mL). The resulting mixture was stirred while warming to 20° C. for 18 h. HPLC after 18 h indicated disappearance of starting material. The resulting slurry was concentrated under reduced pressure removing approximately half the total volume. Isopropylacetate (50 mL) was then added and the resulting slurry was stirred for 1 h at 20° C. The solid was filtered and washed with isopropyl acetate (20 mL) under nitrogen. The solids were dried using a filter press with a nitrogen stream followed by drying under vacuum at 45° C. to afford 2-[5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-dihydrochloride (3-1g, 9.6 g, 98%). MS (ES+) 335.2 (M+H)+. 1H NMR (CD3OD) δ 2.16-2.23 (m, 5H), 2.59 (br s, 1H), 2.78-2.80 (m, 3H), 3.12 (br s, 1H), 3.19-3.24 (m, 4H), 3.37-3.49 (m, 1H), 4.14-4.23 (m, 3H), 4.49 (br s, 1H), 5.11 (br s, 1H), 7.84 (d, 1H), 8.30-8.34 (m, 2H), 8.46 (s, 1H), 9.36 (s, 1H).