Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:25])([CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)[CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[CH2:26]([Li])CCC.CI.[Cl-].[NH4+]>CCOCC.CCCCCC>[CH3:1][Si:2]([CH3:25])([CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH3:26])=[CH:17]1)[CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: C[Si](C)(C1C=Cc2ccccc21)C1c2ccccc2-c2ccccc21
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CI
Solvent: CCOCC
Product: CC1=CC([Si](C)(C)C2c3ccccc3-c3ccccc32)c2ccccc21
Yield: 89 %

Procedure:
A 200 ml four-necked flask equipped with a reflux tube, a thermometer and a dropping funnel was thoroughly purged with nitrogen and dried. To the flask, dimethyl(1-indenyl)(9-fluorenyl)silane (2.00 g, 5.91 mmol) synthesized above and dehydrated ether (50 ml) were introduced. To the flask was dropwise added a hexane solution of n-butyllithium (6.21 mmol) at -40° C. with stirring. The temperature of the reaction liquid was allowed to spontaneously and slowly rise to room temperature. After stirring over night, the reaction liquid became a yellow solution. To the solution, methyl iodide (3.78 g, 26.6 mmol) was added and the temperature of the system was allowed to spontaneously and slowly rise to room temperature, followed by stirring for one day. The reaction liquid became an orange solution. To the resulting solution, 100 ml of ether and 100 ml of a saturated aqueous solution of ammonium chloride were added and the mixture was introduced into a separatory funnel to separate an organic phase. The organic phase was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off, it was purified by column chromatography (developer: hexane) to obtain two kinds of isomers (one was a colourless transparent liquid, the other was a yellow liquid) totalling to 1.85 g (yield: 89%).
Reaction SMILES: B.CSC.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[CH3:26][C:27]1([CH3:48])[O:32][C:31]2[CH:33]=[CH:34][C:35]([C:37](=[O:47])[CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:36][C:30]=2[CH2:29][O:28]1.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:26][C:27]1([CH3:48])[O:32][C:31]2[CH:33]=[CH:34][C:35]([C@@H:37]([OH:47])[CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[CH:36][C:30]=2[CH2:29][O:28]1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc2c(c1)COC(C)(C)O2
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: CSC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H](O)c1ccc2c(c1)COC(C)(C)O2
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A 2M solution of borane-dimethyl sulphide in THF (28 ml) was added slowly to a 1 M solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole in toluene (56 ml) at 0° C. under nitrogen. A solution of tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate, (108.2 g) in THF (1.3 liters) was added slowly keeping the temperature below 5° C. followed by 2M solution of borane-dimethyl sulphide in THF (252 ml) over 50 min. After 1 h, 2M HCl (170 ml) was added with cooling and the mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3 solution and brine and dried (MgSO4). The solution was concentrated and the product purified by chromatography on flash silica gel (800 g), eluting successively with hexane:ethyl acetate (4:1 then 3:1) to give the title compound (93.3 g), LCMS RT=3.31 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3ccc([N+](=O)[O-])cc23)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C#Cc1cccc(Nc2ncnc3ccc(N)cc23)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixture of N-(3-ethynylphenyl)-6-nitroquinazolin-4-amine (1.00 g, 3.45 mmol) and SnCl2.2H2O (3.10 g, 13.8 mmol) in ethyl acetate (35 mL) was refluxed for 2 h and then cooled to room temperature. The pH was adjusted to 9-10 by treatment with 5% aqueous NaHCO3. The mixture was subjected to extraction with EtOAc. The combined organic layers were washed with saturated brine and H2O and dried. The solvent was removed under reduced pressure to give 0.79 g (89%) of N4-(3-ethynylphenyl)quinazoline-4,6-diamine as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:33][N:34]1[C:38]([CH2:39][NH2:40])=[CH:37][N:36]=[CH:35]1>>[CH3:33][N:34]1[C:38]([CH2:39][NH:40][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([C:11]3[O:12][C:8]([CH3:7])=[C:9]([CH2:22][S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:24])=[O:25])[N:10]=3)=[CH:14][CH:15]=2)=[CH:37][N:36]=[CH:35]1
Reactant: Cn1cncc1CN
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cncn4C)cc3)oc2C)cc1
Yield: 82.3 %

Procedure:
Reaction of oxalyl chloride (111 λL, 1.27 mmol) and benzoic acid 4 (318 mg, 0.85 mmol) with subsequent coupling to (1-methyl-1H-imidazol-5-yl)methylamine (104 mg, 0.94 mmol) gave benzamide 15 (325 mg, 82%) as a white powder: mp (EtOAc) 240-242° C.; 1H NMR δ 8.93 (t, J=5.3Hz, 1 H, CONH), 7.97 (br d, J=8.5Hz, 2 H, H-2, H-6), 7.87 (br d, J=8.5Hz, 2 H, H-3, H-5), 7.67 (br d, J=8.3 Hz, 2 H, H-2′, H-6′), 7.54 (s, 1 H, H-2″), 7.42 (br d, J=8.3Hz, 2 H, H-3′, H-5′), 6.84 (s, 1 H, H-4″), 4.62 (s, 2 H, CH2SO2), 4.48 (d, J=5.3Hz, 2 H, CH2N), 3.62 (s, 3 H, NCH3), 2.40 (s, 3 H, CH3), 2.13 (s, 3 H, CH3); 13C NMR δ 165.1, 157.9, 149.8, 144.4, 138.1, 135.5, 135.4, 129.5 (2), 128.7, 128.6, 128.1 (2), 128.0 (2), 127.7, 125.9, 125.2 (2), 52.8, 32.5, 30.9, 20.9, 9.5; MS m/z 465.5 (MH+, 100%). Anal. calcd for C24H24N4O4S: C, 62.05; H, 5.21; N, 12.06. Found: C, 62.42; H, 5.24; N, 12.12%.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13](C2C=CC=CC=2)[N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[C:29](C1N2CCNCC2=C(C(N[C@@H](C(C)(C)C)C(NC)=O)=O)N=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:29]([C:13]1[N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C:15]2=[C:11]([C:9]([NH:8][C@@H:3]([C:2]([CH3:1])([CH3:28])[CH3:27])[C:4]([NH:6][CH3:7])=[O:5])=[O:10])[N:12]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(C(=O)c2ccccc2)n2c1CNCC2)C(C)(C)C
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C)CC2)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1nc(C(=O)c2ccccc2)n2c1CN(C)CC2)C(C)(C)C

Procedure:
Compound 289 was synthesized in the same manner as described above for Compound 48 in Example 5 except that 25C was used in place of Compound 2. 1H-NMR (400 MHz, CD3OD) δ: 1.04 (s, 9H), 2.55 (s, 3H), 2.75 (d, 3H), 2.93 (t, 2H), 4.03 (d, 2H), 4.35 (d, 1H), 4.56 (t, 2H), 7.53 (t, 2H), 7.64 (m 1H), 7.86 (d, 1H), 8.19 (m, 1H), 8.31 (d, 2H); LCMS (+ESI) m/z 412.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:33]3[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=3)([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[OH:26])[CH:8]=2)[N:3]=1.C1(C)C=CC=CC=1.[CH3:46][O-:47].[Na+]>CCOC(C)=O>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:33]3[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=3)([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[OH:26])[CH:8]=2)[N:3]=[C:2]([O:47][CH3:46])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: C[O-]
Reactant: Cn1cncc1C(O)(c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1)c1ncccn1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1nc2ccc(C(O)(c3ncccn3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (58 mg, 0.107 mmol, Example 130), toluene (2 mL), and sodium methoxide (116 mg, 2.14 mmol) were combined in a round bottom flask equipped with a stirbar and condenser under an N2 atmosphere. The reaction contents were heated to reflux and refluxed overnight. The reaction was cooled to room temperature and the contents were transferred to a separatory funnel with EtOAc dilution, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound. MS (ESI): mass calcd. for C29H24ClN7O2, 537.2. m/z found, 538.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ ppm 8.84 (d, J=4.9 Hz, 2H), 8.39 (d, J=1.8 Hz, 1H), 8.13-8.07 (m, 1H), 7.86 (dd, J=8.8, 2.0 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.66 (d, J=1.3 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H), 7.42 (t, J=4.9 Hz, 1H), 7.32 (d, J=8.6 Hz, 2H), 6.50-6.45 (m, 1H), 6.42 (s, 1H), 4.27 (s, 2H), 4.04 (s, 3H), 3.39 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18](I)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:19]4[C:18]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cccnc43)CC2)ccc1Cl
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)Cn3nc(N4CCOCC4)c4cccnc43)CC2)ccc1Cl
Temperature: 80 °C

Procedure:
A mixture of 1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (102.4 Mg), morpholine (0.20 mL), Xantphos (35 Mg), Pd2(dba)3 (18.3 Mg) and Cs2CO3 (97 Mg) in THF (1 mL) was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature, diluted by EtOAc (3 mL) and filtered. The filtrate was evaporated in vacuo. The crude residue was purified by flash chromatography (silica, Hexane/EtOAc) to provide the title compound as a white powder: LCMS (ES) M+H 471.6, Rf 2.043 min (Agilent Zorbax SB-C18, 2.1×50 Mm, 5μ, 35° C., 1 mL/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B, A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:30])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:29])[CH:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][CH2:13]1.OC1C=CC=CC=1[C@@H](CC)C(O)=O>>[OH:28][C@H:19]([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:18]([N:15]1[CH2:14][CH2:13][N:12]([CH2:11][C:10]([NH:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[O:30])[CH2:17][CH2:16]1)=[O:29]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)C(O)CCc2ccccc2)CC1
Agent: CC[C@@H](C(=O)O)c1ccccc1O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)[C@H](O)CCc2ccccc2)CC1

Procedure:
Compound 18 was prepared in the manner of compound 7 substituting R-2-hydroxy-4-phenylbutyric acid for (R)-2-hydroxy-phenylbutyric acid in part C to afford compound 18. Mass spectrum (M+1)=410.44.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:10]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[C:17]1([CH3:20])[CH:18]=[CH:19][C:14]([C:13]#[C:12][CH2:11][N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cnn(CC#Cc2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C#CCn2cc(C(=O)O)cn2)cc1
Yield: 90.2 %

Procedure:
1-(3-p-Tolyl-prop-2-ynyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.226 g, 0.84 mmol) was dissolved in a mixture of solvents THF: methanol:water (3:1:1, 10 ml) and LiOH (0.071 g, 1.7 mol) was added to the reaction mixture with stirring. The reaction mixture was then stirred at 20-25° C. for 2 hours. Solvents were evaporated and the residue was diluted with water (0.5 ml) and acidified with dil. HCl, filtered and dried to obtain off white precipitate, 1-(3-p-Tolyl-prop-2-ynyl)-1H-pyrazole-4-carboxylic acid (0.182 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([O:20]C)=[O:19])=[CH:7][N:8]2C(OC(C)(C)C)=O)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.Cl[CH2:30][CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([OH:20])=[O:19])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:30][CH2:31][N:32]2[CH:36]=[N:35][CH:34]=[N:33]2)=[CH:24][CH:23]=1
Reactant: ClCCn1cncn1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2cc(Cl)c(-c3ccc(O)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCn4cncn4)cc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 3.5 %

Procedure:
A vial was charged with 1-tert-butyl 3-methyl 6-chloro-5-(4-hydroxyphenyl)-1H-indole-1,3-dicarboxylate (30 mg, 0.075 mmol), 1-(2-chloroethyl)-1H-1,2,4-triazole (15 mg, 0.12 mmol) and tetrahydrofuran (1 mL). Cesium carbonate (64 mg, 0.18 mmol) was then added and the vial was sealed and stirred at room temperature for 3 hours then heated to 70° C. for 18 h. The reaction was filtered and the filtrate was concentrated in vacuo. Methanol (1 mL) and 1.0 M sodium hydroxide (0.3 mL, 0.3 mmol) were added and the reaction stirred for 18 h at 70° C. The reaction was then concentrated in vacuo and purified by reverse phase HPLC to provide 1 mg of the title compound. MS (ES+) 383.1 (M+H)+. Retention time=2.38 minutes (Waters Atlantis dC18 4.6×50, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:20](=[S:21])[N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=3)[C:18](=[O:34])[C:14]32[CH2:17][CH2:16][CH2:15]3)=[CH:9][CH:8]=1.CCCCCC>ClCCl.[H-].C([Al+]CC(C)C)C(C)C>[O:34]=[C:18]1[C:14]2([CH2:17][CH2:16][CH2:15]2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][CH:3]=[O:2])=[CH:12][CH:11]=2)[C:20](=[S:21])[N:19]1[C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1
Reactant: COC(=O)CCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC=O)cc3)C2=S)cc1C(F)(F)F
Temperature: 21 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-phenyl}-butyric acid methyl ester (67) [ND-4] (61 mg, 0.12 mmol) in dichloromethane (5 mL), 1M diisobutylaluminum hydride (DIBAL) solution in hexane (0.16 mL, 0.16 mmol) was added at −78° C. After 30 min, the reaction mixture was quenched with saturated Rochelle's salt solution. The resulting mixture was stirred at 21° C. until both phases were clearly separated and the organic layer was clear. After extraction, the separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude mixture of (66) and (68) was purified by flash column chromatography (hexane:ethyl acetate,
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[C:37]([C:38]#[N:39])=[CH:36][N:35]=[CH:34][CH:33]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:38]#[N:39])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(c2ccncc2C#N)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccncc4C#N)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile following a procedure analogous to that described in Example 28. LC (method 10): tR=1.64 min; Mass spectrum (ESI+): m/z=407 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[S:18][C:17]([S:19]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:21])=[O:20])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 5-chlorothiophene-2-sulfonyl chloride as described in the synthetic METHOD B to give a white solid (24.3 mg) with purity >90%. MS (pos) m/z 367.1, 369.1.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.C(N(CC)S(C1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(S(=O)(=O)N(CC)CC)=CC=3)=CC=2C(O)=O)=CC=1)(=O)=O)C>[CH:3]1[C:2]([Cl:1])=[CH:28][C:27]2[C:9]([C:8]3[C:7]([NH:6][C:5]=2[CH:4]=1)=[CH:15][C:14]1[C:16]([C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:13]=1[CH:12]=3)=[O:18])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Agent: CCN(CC)S(=O)(=O)c1ccc(Nc2cc(C(=O)O)c(Nc3ccc(S(=O)(=O)N(CC)CC)cc3)cc2C(=O)O)cc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 95 °C
Reaction time: 0.08 h
Yield: 102.2 %

Procedure:
To 720 g of polyphosphoric acid (116.5%) heated at 90° C. were added 12.0 g of 2,5-di[4-(N,N-diethylsulfamoyl)anilino]terephthalic acid. The mixture was stirred for five minutes, after which 120 g of 2,5-di(4-chloroanilino)terephthalic acid were added over a period of approximately 45 minutes, the temperature being maintained below 110° C. by adjustment of the addition rate. The reaction mixture was held at 113° C. for five hours and then cooled to 95° C. To this mixture was added 89.4 g of phosphoric acid (75%) dropwise over a period of 20 minutes. The resultant melt was allowed to stir for 15 minutes at 92° C. and then poured slowly into 1240 g of methanol, the temperature being maintained below reflux by adjustment of the addition rate. The slurry was allowed to cool to room temperature and stand for 16 hours. The pigment slurry was heated at reflux for one hour, cooled below 65° C., diluted with water, collected by filtration, and washed with water until free of acid. The resultant wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 112 g of 2,9-dichloroquinacridone as a magenta pigment.
Reaction SMILES: [NH2:1][CH:2]([CH3:13])[CH:3]([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26](I)=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([O:12][CH:3]([CH2:4][O:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:2]([NH2:1])[CH3:13])=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: CC(N)C(O)COc1ccccc1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Product: CC(N)C(COc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1

Procedure:
Prepared as described in Example 1 from (2RS,3RS)-3-amino-1-phenoxy-butan-2-ol (250 mg, 1.37 mmol), and 1-(4-fluorophenyl)-5-iodoindazole (557 mg, 1.64 mmol). Yield 157 mg (29
Reaction SMILES: [C:1]([C:8]([NH2:11])([OH:10])C)(OC(C)(C)C)=O.[CH:12]1[CH:13]=[CH:14][C:15]([NH:22][C:23]2[C:24]([Cl:30])=[CH:25][CH:26]=[CH:27][C:28]=2[Cl:29])=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=1.[ClH:31].C(OCC)(=O)C.C(OCC)C.CCCCCC>ClCCl>[NH2:11][CH:8]([OH:10])[CH3:1].[CH:12]1[CH:13]=[CH:14][C:15]([NH:22][C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=1.[ClH:31]
Reactant: CC(C)(C)OC(=O)C(C)(N)O
Agent: Cl
Agent: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(N)O
Reaction time: 2.5 h

Procedure:
In 5 ml of dichloromethane, 2.108 g (4.80 mmol) of the Boc-aminoethanol-diclofenac obtained above was dissolved, and 20 ml of 4 M hydrochloric acid/ethyl acetate was added thereto under ice-cooling, followed by stirring for 2.5 hours. Diethyl ether and hexane were added thereto for precipitation, and the precipitate was dried under reduced pressure to give 1.775 g (98%) of the titled compound. The structure was identified by 1H-NMR.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:13][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: N#CCc1cccc(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To an ice-cold solution of (3-hydroxymethylphenyl)acetonitrile (0.97 g, 7.3 mmol) in THF (35 mL) was added CBr4 (2.5 g, 7.7 mmol) and Ph3P (2.0 g, 7.7 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 1:9 to 1:4 EtOAc/hexanes) provided (3-bromomethylphenyl)acetonitrile as a clear oil (0.89 g, 58%): 1H NMR (300 MHz, MeOD) δ 7.47-7.29 (m, 1H), 7.27 (s, 1H), 6.97 6.82 (m, 1H), 4.87 (s, 2H), 3.91 (s, 2H).