Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH2:5]1[C@@H:15]2[C@H:9]([CH:10]=[CH:11][C:12]3[C:13]4[N:14]2[C:16]2[CH:25]=[CH:24][N:23]=[CH:22][C:17]=2[C:18]=4[CH2:19][CH2:20][CH:21]=3)[CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.O>CN(C=O)C>[CH2:3]([CH:7]1[CH2:8][CH:9]2[CH:10]=[CH:11][C:12]3[C:13]4[N:14]([C:16]5[CH:25]=[CH:24][N:23]=[CH:22][C:17]=5[C:18]=4[CH2:19][CH2:20][CH:21]=3)[CH:15]2[CH2:5][CH2:6]1)[C:2]#[CH:1]
Reactant: C#CCBr
Reactant: C1=C[C@@H]2CCCC[C@H]2n2c3c(c4cnccc42)CCC=C13
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCC1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Propargyl bromide, 2.38 g, was added to a solution of (±)-trans-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine (5.52 g) and triethylamine (3ml) in 90 ml DMF. The reaction mixture was stirred at room temperature for 41/2 hours. Some precipitate had formed. The reaction mixture was poured into 300 ml of cold water. A solid precipitated which was filtered off and washed with cold water. Recrystallization from 300 ml ethanol gave 4.05 g of the title compound as pale yellow needles, m.p. 160°-161.5°. An analytical sample was recrystallized again from ethanol to give almost colorless needles, m.p. 162°-163° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)C(C)C)(C)C.[CH3:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([OH:25])=O.Cl.CN(C)CCCN=C=NCC.[NH2:46][CH:47]1[N:53]=[C:52]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:51]2[CH:60]=[CH:61][CH:62]=[CH:63][C:50]=2[N:49]([CH2:64][CH2:65][CH2:66][C:67]([F:70])([F:69])[F:68])[C:48]1=[O:71]>C1COCC1.C(Cl)Cl>[C:30]([O:29][C:27]([NH:26][C@H:22]([C:23]([NH:46][CH:47]1[N:53]=[C:52]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:51]2[CH:60]=[CH:61][CH:62]=[CH:63][C:50]=2[N:49]([CH2:64][CH2:65][CH2:66][C:67]([F:69])([F:68])[F:70])[C:48]1=[O:71])=[O:25])[CH3:21])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CCCC(F)(F)F)C1=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(CCCC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
To a solution of HOBt-H2O (373 mg, 2.76 mmol), N,N-diisopropylethylamine (481 uL, 2.76 mmol) and N-t-BOC-L-alanine (522 mg, 2.76 mmol) in 10 mL of anhydrous THF at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI; 527 mg, 2.76 mmol) in one portion. After stirring 5 min., a solution of 3-amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (1.05 g, 2.91 mmol) in 10 mL of anhydrous THF was added via syringe and the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with 100 mL methylene chloride, extracted sequentially with 10% citric acid, saturated sodium bicarbonate, water and brine and then dried over sodium sulfate. Purification of the crude product using silica gel chromatography (10%-30% ethyl acetate/methylene chloride) gave 1.28 g (83%) of a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:25]=[CH:24][C:23]3[C:14](=[CH:15][C:16]4[C:17]([CH3:29])([CH3:28])[CH2:18][CH2:19][C:20]([CH3:27])([CH3:26])[C:21]=4[CH:22]=3)[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].I[CH2:31][CH2:32][CH3:33]>>[CH2:31]([O:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:25]=[CH:24][C:23]3[C:14](=[CH:15][C:16]4[C:17]([CH3:29])([CH3:28])[CH2:18][CH2:19][C:20]([CH3:27])([CH3:26])[C:21]=4[CH:22]=3)[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH2:32][CH3:33]
Reactant: CCCI
Reactant: COC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)cc1O
Product: CCCOc1cc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)ccc1C(=O)OC
Yield: 52.8 %

Procedure:
Following the basic procedure of Example 12, by reacting 2 g (5.1 mmol) of methyl 2-hydroxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)benzoate with 600 μl (6.1 mmol) of 3-iodopropane, 1.16 g (54%) of methyl 2-propyloxy-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthryl)benzoate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCCN2CCCCC2)c2ccc(C#CCO)cc2c1=O
Temperature: 90 °C
Reaction time: 38 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.367 g) is dissolved in DMF (10 mL), and K2CO3 (0.55 g) and N-(3chloropropyl)piperidine hydrochloride (0.408 g) are added. The reaction mixture is heated to 90° C. for 10 h, and then allowed to stir at room temperature for 38 h. Water is added and a precipitate formed. The precipitate is filtered and allowed to dry at room temperature and then under reduced pressure to give 0.187 g of a solid. The solid is dissolved in CHCl3 and filtered to remove 0.045 g of a precipitate. The filtrate is concentrated in vacuo and crystallized from ethyl acetate to give 0.065 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([I:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([I:12])[C:5]([O:11][CH2:15][CH3:16])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(I)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1I
Temperature: 60 °C
Yield: 91.7 %

Procedure:
1-(5-Chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (18.9 g, 60.9 mmol, from Example 60, Step 1) was dissolved in DMF (61 mL). Iodoethane (7.3 mL, 91 mmol) was added followed by potassium carbonate (17.0 g, 120 mmol). The reaction was heated at 60° C. for 1 hour. The mixture was cooled to room temperature, diluted with ether, washed with water, dried over MgSO4, concentrated. The resulting residue was purified on silica gel (eluting with 0 to 10% EtOAc in hexanes) to give the desired product (18.9 g, 91.7%). LCMS calculated for C11H13ClIO2 (M+H)+: m/z=339.0. found: 339.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][C@@H:21]([C:23]([O:25]C(C)(C)C)=[O:24])[CH3:22])=[O:19])=[C:5]2[OH:30]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:17])[C:6]([C:18]([NH:20][C@@H:21]([C:23]([OH:25])=[O:24])[CH3:22])=[O:19])=[C:5]2[OH:30]
Reactant: C[C@@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O)C(=O)O
Yield: 89.4 %

Procedure:
1,1-Dimethylethyl N-((6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)-D-alaninate (501 mg, 1149 μmol) was dissolved in TFA at ambient temperature for 30 minutes before it was concentrated, precipitated with hexanes, filtered, washed with hexanes, and dried in a vacuum oven to give the title compound (390 mg) as a white solid. MS (m/z)=380 (M+H)+. Calculated for C18H18ClNO6 379.08.
Reaction SMILES: [C:1]([NH:4][C:5]1S[C:8]2[CH2:10][CH:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:12][CH2:13][C:7]=2[C:6]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:3])[CH3:2]>[Ni]>[CH3:21][O:20][C:18](=[O:19])[CH:6]([CH:7]1[CH2:13][CH2:12][CH:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:8]1)[CH2:5][NH:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)c1c(NC(C)=O)sc2c1CCC(C(C)(C)C)C2
Agent: [Ni]
Product: COC(=O)C(CNC(C)=O)C1CCC(C(C)(C)C)CC1
Yield: 98.1 %

Procedure:
Methyl 2-acetamido-6-tert-butyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.8286 g, 2.68 mmol) was reductively desulfurized using Raney nickel to yield the title compound as a sticky white solid (0.7466 g, 2.63 mmol, 98.3%); mp: 73-75° C.; TLC: Rf=0.70 (Solvent I), 0.33 (Solvent J); IR (cm−1): 3261 (NH), 2943 (CH aliphatic), 1735 (ester C═O), 1648 (amide C═O), 1H nmr (CDCl3): δ 5.88 (br s, 1H), 3.69 (s, 3H), 3.53 (m, 1H), 3.41 (m, 1H), 3.34 (m, 1H), 2.44 (m, 1H), 1.94 (s, 3H), 1.77 (m, 2H), 1.63 (m, 1H), 1.50 (m, 1H), 1.27 (t, 1H, J=7.1 Hz), 1.00 (m, 4H), 0.82 (s, 9H).
Reaction SMILES: C1(NC2N=C(C3C=CC=CN=3)C=C(C3C=NC=C(C#CCN4CCN(C(C)C)CC4)C=3)C=2)CC1.Br[C:36]1[CH:37]=[C:38]([C:42]2[CH:47]=[C:46]([NH:48][CH:49]([CH3:51])[CH3:50])[N:45]=[C:44]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=3)[CH:43]=2)[CH:39]=[N:40][CH:41]=1.C(N1CCN(CC#C)CC1)(C)C.[C:70]([N:74]1[CH2:79][CH2:78][N:77]([CH2:80][C:81]#[CH:82])[CH2:76][CH2:75]1)([CH3:73])([CH3:72])[CH3:71]>>[C:70]([N:74]1[CH2:75][CH2:76][N:77]([CH2:80][C:81]#[C:82][C:36]2[CH:37]=[C:38]([C:42]3[CH:47]=[C:46]([NH:48][CH:49]([CH3:51])[CH3:50])[N:45]=[C:44]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=4)[CH:43]=3)[CH:39]=[N:40][CH:41]=2)[CH2:78][CH2:79]1)([CH3:73])([CH3:72])[CH3:71]
Reactant: CC(C)Nc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Reactant: C#CCN1CCN(C(C)(C)C)CC1
Agent: C#CCN1CCN(C(C)C)CC1
Agent: CC(C)N1CCN(CC#Cc2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)CC1
Product: CC(C)Nc1cc(-c2cncc(C#CCN3CCN(C(C)(C)C)CC3)c2)cc(-c2ccccn2)n1

Procedure:
This compound is prepared analogously to Cyclopropyl-{5″-[3-(4-isopropyl-piperazin-1-yl)-prop-1-ynyl]-[2,2′;4′,3″]terpyridin-6′-yl}-amine (Example 2.127) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) with (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-isopropyl-amine (Example 2.46, step1) and by replacing 1-isopropyl-4-(prop-2-ynyl)piperazine (Intermediate D1) with 1-tert-Butyl-4-prop-2-ynyl-piperazine (Intermediate D2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[C:8]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])[C@@H:12]([CH3:22])[CH2:11][CH2:10]3)[CH:6]=1.Br[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]Br.[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:19]1([C:17]([N:13]2[C:14]3[C:9](=[C:8]([O:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:7]([N:5]4[CH:6]=[C:2]([N:1]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:3]=[N:4]4)=[CH:16][CH:15]=3)[CH2:10][CH2:11][C@@H:12]2[CH3:22])=[O:18])[CH2:20][CH2:21]1
Reactant: C[C@H]1CCc2c(ccc(-n3cc(N)cn3)c2Oc2ccccc2)N1C(=O)C1CC1
Reactant: BrCCNCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: C[C@H]1CCc2c(ccc(-n3cc(N4CCNCC4)cn3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-(6-(4-amino-1H-pyrazol-1-yl)-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.020 g, 0.05 mmol), bis(2-bromoethyl)amine (0.020 g, 0.09 mmol), sodium iodide (0.003 g, 0.02 mmol), and cesium carbonate (0.084 g, 0.26 mmol) in acetonitrile (2 mL) stirred overnight at 85° C. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum, and the residue was purified by preparative thin layer chromatography (eluting with 10% methanol/dichloromethane). The product was further purified by preparative-HPLC with the following conditions: Column: XBridge RP C18, 19×150 mm, 5 um; Mobile Phase: water (0.05% ammonium bicarbonate) and acetonitrile (5% to 60% acetonitrile in 7.0 min, flow rate: 20 mL/min); Detector: UV220&254 nm. This afforded (5)-cyclopropyl(2-methyl-5-phenoxy-6-(4-(piperazin-1-yl)-1H-pyrazol-1-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.0011 g, 5%) as a light yellow solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.96-0.82 (m, 1H), 0.91-1.06 (m, 2H), 1.15-1.22 (m, 3H), 1.31-1.38 (m, 2H), 1.42-1.51 (m, 1H), 1.95-2.07 (m, 1H), 2.21-2.32 (m, 1H), 2.33-2.45 (m, 1H), 2.73-2.92 (m, 9H), 4.55-4.65 (m, 1H), 6.71-6.79 (m, 2H), 6.93-7.01 (m, 1H), 7.19-7.26 (m, 2H), 7.40 (s, 1H), 7.45-7.50 (m, 1H), 7.54-7.63 (m, 2H). MS (ESI, pos. ion) m/z 458 [M+H]+.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[S:87]1[CH:91]=[N:90][N:89]=[C:88]1[NH:92][C:93](=[O:97])[C:94]([OH:96])=O>>[S:87]1[CH:91]=[N:90][N:89]=[C:88]1[NH:92][C:93](=[O:97])[C:94]([NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1)=[O:96]
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)C(=O)Nc1nncs1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)C(=O)Nc3nncs3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 21 %

Procedure:
The title compound was prepared in 21% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-(1,3,4-thiadiazol-2-ylamino)-2-oxoacetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 683.6 (M−H)−, 1.77 min (method 9). 1H NMR (500 MHz, 2:1 MeOD:CDCl3) δ=9.13 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.45 (s, 1H), 7.21 (d, J=8.2 Hz, 2H), 5.37-5.24 (m, 1H), 4.81-4.78 (m, 1H), 4.67 (s, 1H), 2.67-2.56 (m, 2H), 2.55-2.47 (m, 1H), 2.15 (dd, J=6.4, 17.1 Hz, 1H), 1.99-1.90 (m, 1H), 1.82 (dd, J=10.5, 16.3 Hz, 3H), 1.74 (s, 3H), 1.71 (br. s., 1H), 1.59-1.44 (m, 9H), 1.44-1.39 (m, 1H), 1.30-1.24 (m, 1H), 1.22-1.14 (m, 2H), 1.10 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]=[C:8]([CH3:11])[CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](OC)([O:16][CH3:17])([O:14]C)[CH3:13].C(O)(=O)CC>>[CH3:11][C:8](=[CH2:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][C:12]([O:16][CH3:17])=[O:14]
Reactant: COC(C)(OC)OC
Reactant: CC(=Cc1ccccc1)CO
Solvent: CCC(=O)O
Product: C=C(C)C(CC(=O)OC)c1ccccc1
Yield: 122.4 %

Procedure:
3-Phenyl-2-methyl-2-propen-1-ol (50 g, 0.32 mol) and trimethyl orthoacetate (263 g, 2.2 mol) were heated together in the presence of propionic acid (0.3 ml) in a bath at 145° C. for 6 hours, while distilling the methanol formed during the reaction. After removing the residual methanol and the excess orthoacetate under vacuum, the product was purified by distillation through a 20-cm Widmer column. 80 g of the desired product were obtained (yield=78%). B.P.=55° C./0.001 mbar
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][C:17]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)=[CH:16][CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([NH2:43])([CH3:42])([CH3:41])[CH3:40]>CO>[C:39]([NH:43][CH2:26][CH:25]([OH:27])[CH2:24][O:23][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12]([C:11]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=1)=[CH:21][C:20]2=[O:22])([CH3:42])([CH3:41])[CH3:40]
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2ccc(OCC3CO3)cc12
Reactant: CC(C)(C)N
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc2oc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)cc(=O)c2c1

Procedure:
3′,4′-Dibenzyloxy-6-(2,3-epoxy-propoxy)-flavone, 30 (1.5 g, 3 mmol) and tert-butyl amine (0.96 mL, 9 mmol) in dry methanol (125 mL) were reacted in a similar manner to that described under 34 to afford 39. Yield 1.5 g (89%); mp 156-157° C.; MS (FAB) 580 (M++1); IR (KBr) 3404, 1621; 1H NMR (200 MHz, CDCl3) δ 7.51-7.26 (m, 15H), 6.97 (d, J=8.9 Hz, 1H), 6.62 (s, 1H), 5.22 (s, 2H), 5.20 (s, 2H), 4.26-4.22 (m, 1H), 4.14-4.10 (m, 2H), 3.07-2.86 (m, 2H), 1.29 (s, 9H). Analysis Calcd for C36H37NO6: C, 74.59; H, 6.43; N, 2.42. Found: C, 74.61; H, 6.62; N, 2.36.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5](=[O:15])[C:6]([CH3:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CC(C)=O.CC(C)([O-])C.[K+].[C:26]1([S:32]Cl)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.O>[C:8]1([C:6]2([CH3:14])[C:5](=[O:15])[N:4]([S:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:3]([S:2][CH3:1])=[N:7]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClSc1ccccc1
Reactant: CSC1=NC(C)(c2ccccc2)C(=O)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CSC1=NC(C)(c2ccccc2)C(=O)N1Sc1ccccc1
Reaction time: 1 h

Procedure:
0.6 g (2.7 mmol) of 2-methylthio-4-methyl-4-phenyl-2-imidazolin-5-one in solution in 50 ml of anhydrous tetrahydrofuran (THF) is charged to a 100 ml, three-necked, round-bottomed flask under an inert atmosphere. The solution is stirred with a magnetic stirrer and is cooled to 0° C. (ice bath+acetone). 0.30 g (1 molar equivalent) of potassium tert-butoxide is added and the mixture is stirred for 10 minutes at 0° C. A solution containing 0.40 g of phenylsulfenyl chloride (phenylthio chloride) and 10 ml of anhydrous THF is then run in. The mixture is then left to return to room temperature for one hour. The reaction mixture is run into 100 ml of water. Extraction is carried out with 100 ml of ethyl acetate. The organic phase is washed 4 times with water and dried over sodium sulfate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)=[O:17]>>[O:17]=[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)[CH:15]([NH:14][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=1
Reactant: NC(Cc1cccc(C(F)(F)F)c1)C(=O)N1CCSC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: O=C(NC(Cc1cccc(C(F)(F)F)c1)C(=O)N1CCSC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-3(3-trifluoromethyl-phenyl)-1-thiazolidin3yl-propan-1-one.
Reaction SMILES: [OH:1]CCC1C=CC(CCO)=CC=1.C1N2CCN(CC2)C1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: OCCc1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a stirred solution of the intermediate from Step A in THF (50 mL) was added DABCO (1.51 g, 13.5 mmol) and then p-toluenesulfonyl chloride (50 mL). The resulting mixture was stirred overnight at room temperature and then filtered to remove precipitated hydrochloride salts. The filtrate was concentrated under reduced pressure and DCM (50 mL) was added to the residue. The organic layer was then washed with water (1×100 mL), saturated NaCl (1×100 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The resulting material was purified by silica gel chromatography (70% EtOAc/hexane) to afford 1.25 g of the title intermediate (43% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[CH:38]1([CH2:43][CH2:44][C:45](Cl)=[O:46])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:45](=[O:46])[CH2:44][CH2:43][CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Product: CC(C)(Cc1c(C(=O)CCC2CCCC2)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy) indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using 3-cyclopentylpropanoyl chloride in place of trimethylacetyl chlcride in Step B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])([OH:24])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])([OH:24])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@](O)(CS(C)(=O)=O)C4)n3)c3cc(Cl)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)C[C@@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-(methylsulfonylmethyl)cyclohexanol, 49f, (0.045 g, 0.074 mmol) in MeOH (2 mL) was added NaOMe (2 mL of 25% w/v, 9.255 mmol). The reaction mixture was allowed to stir at room temperature for 5 minutes, after which the mixture was quenched with the addition of aqueous saturated NH4Cl solution and then diluted with EtOAc. The layers were separated and the organic was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-10% MeOH/CH2Cl2 gradient).