Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH:11](O)[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@@H:14]1[CH2:26][OH:27].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH:11]1[O:27][CH2:26][C@H:14]2[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:17][CH2:18][N:13]2[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2Cl)[C@@H](CO)C1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN2CC(c3ccc(F)c(C#N)c3Cl)OC[C@H]2C1
Temperature: 100 °C

Procedure:
(3R)-tert-butyl 4-(2-(2-chloro-3-cyano-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (15.6 g, 37.3 mmol) and cyanomethylene tri-n-butyl phosphorane (16.4 g, 67.8 mmol) were dissolved in benzene (90 mL), degassed and heated at 100° C. for 16 h. The reaction mixture was concentrated and chromatographed through a 330 g ISCO Redi-sep column and eluted with 35% EtOAc/hexane to yield the title compound (cis-trans diastereomers mixture). LC-MS (IE, m/z): 396 [M+1]+;
Reaction SMILES: [Na].C([CH:5]1[C:11](=[O:12])[CH:10]2[CH:7]([CH2:8][CH2:9]2)[C:6]1=[O:13])(=O)C>Cl>[CH:7]12[CH2:8][CH2:9][CH:10]1[C:11](=[O:12])[CH2:5][C:6]2=[O:13]
Reactant: CC(=O)C1C(=O)C2CCC2C1=O
Agent: Cl
Agent: [Na]
Product: O=C1CC(=O)C2CCC12

Procedure:
The sodium salt of 3-acetyl-bicyclo[3.2.0]heptane-2,4-dione (Example 50a; 3.2 g; 17.2 mmol) is dissolved in 2N HCl (90 ml) and refluxed for 7 hours, evaporated to dryness, taken up in CH2Cl2 and purified via chromatography (SiO2; eluents: CH2Cl2followed by TBME then TBME/EtOH 95:5) to deliver the title compound as yellow crystals (1.1 g; 51%).
Reaction SMILES: [Mg].Br[C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[P:13]([Cl:16])(Cl)Cl>CCOCC>[C:3]12([P:13]([C:3]34[CH2:12][CH:7]5[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]5)[CH2:4]3)[CH2:10]4)[Cl:16])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: ClP(Cl)Cl
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: [Mg]
Solvent: CCOCC
Product: ClP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
An oven-dried, round-bottom flask was charged with magnesium turnings (15.3 g, 0.63 mol) and 1-bromoadamantane (9.0 g, 0.041 mol). The flask was evacuated and backfilled with argon two times. To the reaction vessel 45 mL ether was added and the mixture was gently refluxed for 15 hours, without mechanical stirring. The resulting solution of Grignard reagent was taken up in a syringe, and added very slowly dropwise to a separate flame-dried, two-necked, round-bottom flask equipped with a reflux condenser which had been charged with PCl3 (0.9 mL, 10 mmol) and 15 mL ether which had been coooled to −40° C. During the addition the temperature was monitored and kept below −25° C. The resulting mixture was stirred for 30 minutes at −45° C., then the cooling bath was removed and the reaction mixture was allowed to warm slowly to room temperature. After stirring for an additional 30 minutes at room temperature, the reaction vessel was placed into a heated oilbath (37° C.) and was gently refluxed for 22 hours. The mixture was cooled to room temperature, and the solution was filtered through a cannula filter. The solvent as well as some of the adamantane byproduct was removed in vacuo, without exposing the product to air to afford crude di-1-adamantylchlorophosphine.
Reaction SMILES: [F:1][CH2:2][C:3]([NH2:11])([CH2:6][CH2:7][CH2:8][O:9][CH3:10])[C:4]#[N:5].C(N(CC)CC)C.[C:19](Cl)(=[O:29])[C:20]1[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:22](Cl)=[O:23]>C(Cl)Cl>[F:1][CH2:2][C:3]([N:11]1[C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]2[C:19]1=[O:29])([CH2:6][CH2:7][CH2:8][O:9][CH3:10])[C:4]#[N:5]
Reactant: COCCCC(N)(C#N)CF
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 2-fluoromethyl-2-amino-5-methoxypentanenitrile (1.62 g, 10 mmol) and triethylamine (2.02 g, 20 mmol) in methylene chloride (30 ml), cooled to -20° C., is added phthaloyldichloride (2.03 g, 10 mmol) in methylene chloride (10 ml). The mixture is allowed to warm up to room temperature overnight. After washing with water, 1N HCl, water again, and drying (Na2SO4), the solvent is removed under reduced pressure to give 2.4 g of crude material. This is purified by chromatography on silica (ethyl acetate/petroleum ether 3:7).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[CH3:22][C:23]1[N:24]=[C:25]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[S:26][C:27]=1[C:28]([F:31])([F:30])[F:29]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:35]2[CH2:36][CH2:37][N:32]([C:25]3[S:26][C:27]([C:28]([F:31])([F:29])[F:30])=[C:23]([CH3:22])[N:24]=3)[CH2:33][CH2:34]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: Cc1nc(N2CCNCC2)sc1C(F)(F)F
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: Cc1nc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3O[C@@H](C)C(F)(F)F)CC2)sc1C(F)(F)F
Yield: 56 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A15) and 1-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 79(g)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white crystalline solid (yield 56%). MS (m/e): 546.0 (M+H+, 100%).
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[CH2:5]([P:8]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:28]=[C:27](I)[N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][N:24]3[CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:15][CH:14]=1)([CH2:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH3:7].CCOC(C)=O>CN(C=O)C.[Zn].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:5]([P:8]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:28]=[C:27]([CH:1]([CH3:3])[CH3:2])[N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][N:24]3[CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:15][CH:14]=1)([CH2:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH3:7]
Reactant: CCCP(=O)(CCC)c1ccc(Nc2nc(I)nc3c2ncn3C2CCCCO2)cc1
Reactant: CC(C)I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCP(=O)(CCC)c1ccc(Nc2nc(C(C)C)nc3c2ncn3C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a oven-dried 10 mL round bottom flask was transferred under Ar 2.88 mL Rieke Zinc (0.14 g Zn, 2.2 mmol, 5 g/100 mL THF) using a 12 gauge needle. Then isopropyl iodide (200 □L, 2 mmol) was added via syringe. The solution turned warm and the content was stirred at rt for 3 h. In a separate flask (25 mL) was dissolved N-(4-(dipropylphosphoryl)phenyl)-2-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.28 g, 0.5 mmol) and PdCl2(PPh3)2 (0.035 g, 0.05 mmol) in 4.0 mL dry DMF. The Zinc reagent was transferred to the reaction via a syringe. The reaction mixture was stirred at rt overnight. 20 mL EtOAc/20 mL water was added to the reaction mixture and the content was filtered through Celite, washed with 1% MeOH/EtOAc (30 mL). The organic layer was separated and washed with water, brine, and dried Na2SO4. The final product was purified on silica gel (4-7.5% MeOH/DCM).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([OH:29])[CH2:10][O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][C:14](=[O:22])[C:13]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([O:50][CH3:51])[C:47]=1[O:48][CH3:49])[C:42](Cl)=[O:43]>C(Cl)(Cl)Cl>[C:23]1([C:13]2[C:14](=[O:22])[O:15][C:16]3[C:21]([C:12]=2[O:11][CH2:10][CH:9]([O:29][C:42](=[O:43])[C:41]2[CH:40]=[C:39]([O:38][CH3:37])[C:47]([O:48][CH3:49])=[C:46]([O:50][CH3:51])[CH:45]=2)[CH2:8][N:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=c1oc2ccccc2c(OCC(O)CN2CCOCC2)c1-c1ccccc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)OC(COc2c(-c3ccccc3)c(=O)oc3ccccc23)CN2CCOCC2)cc(OC)c1OC
Reaction time: 2 h
Yield: 73.4 %

Procedure:
14.2 g. (0.034 mol) of 4-(3'-morpholino-2'-hydroxypropoxy)-3-phenyl-coumarin hydrochloride (Example 32) are placed in 130 ml. of chloroform containing 3.4 g. (0.034 mol) of triethylamine. A solution of 7.83 g. (0.034 mol) of 3,4,5-trimethoxy-benzoyl chloride in 20 ml. of chloroform are then added in 21/2 hours. The mixture is then brought over 2 hours to 40°-50° C. Cooling takes place, the insoluble substance is filtered off, the filtrate is washed with a sodium bicarbonate solution and dried over sodium sulphate. The solvent is evaporated under vacuum and there are obtained 14.3 g. of an oil which cannot be crystallised. Yield 73.4% (theoretical yield 19.5 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[CH2:17]([O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=O)[CH:28]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=1)[CH3:18].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([NH:32][CH3:33])[N:21]=[C:20]3[O:19][CH2:17][CH3:18])[C:9](=[O:11])[N:10]=1
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Reactant: Cc1cccc(Cl)c1CNC1=NC(=O)CS1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4c(C)cccc4Cl)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-(2-chloro-6-methyl-benzylamino)-thiazol-4-one (example 18a, 40.8 mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 30 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 2-(2-chloro-6-methyl-benzylamino)-5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-thiazol-4-one as a light brown solid: 45.9 mg (61.3%), MS: m/e 468 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]=[C:45]=[O:46])=[CH:40][CH:39]=1>ClCCl>[F:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=3)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=2)=[O:46])=[CH:40][CH:39]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.5 %

Procedure:
The 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (20 μL, 0.14 mmol) followed by 4-fluorophenyl isocyanate (14.6 μL 0.13 mmol) were added. The solution was stirred at room temperature for 18 hours. The reaction was filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 26 mg (40%) of the desired N-(4fluorophenyl)-N′-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenyl]urea product as a yellow oil, which was greater than 95% pure by reverse phase HPLC analysis. HRMS calcd. for C25H22F8N3O3: 564.1533 [M+H]+, found: 564.1566. 1H NMR (CDCl3) δ3.7 (m, 2H), 4.1 (m, 1H), 4.7 (m, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.9-7.4 (m, 11H), 7.5 (s, 1H), 7.8 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[N:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].C1C(=O)N([Br:29])C(=O)C1.ClCCl.[Cl-].[Na+].O>ClCCl>[Br:29][C:15]1[CH:14]=[CH:13][C:12]([N:4]([C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=2[CH3:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1N(c1ccccc1)c1ccccc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1N(c1ccc(Br)cc1)c1ccccc1C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 2-methyl-N-phenyl-N-(o-tolyl)aniline (Compound 10) (8.2 g, 30 mmol) in dichloromethane (DCM) (100 mL), was added n-bromosuccinimide (NBS) (5.34 g, 30 mmol) at about 0° C. and stirred for about 4 hours. The resulting mixture was worked up with dichloromethane/brine, dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes to hexanes/dichloromethane 9:1. The desired fraction was collected, and removal of solvent gave a white solid (Compound 11) (10.7 g, in 100% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([CH3:13])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].[C:24]1(=[O:38])[N:28]([CH2:29][C:30](Cl)=[O:31])[C:27](=[O:33])[C:26]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:25]12>C(Cl)(Cl)Cl>[C:14]([C:3]1[C:2]([NH:1][C:30](=[O:31])[CH2:29][N:28]2[C:27](=[O:33])[C:26]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:25]3[C:24]2=[O:38])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:4]=1[CH3:13])(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1[nH]c(-c2ccccc2)c(N)c1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(-c2ccccc2)c(NC(=O)CN2C(=O)c3ccccc3C2=O)c1C(=O)c1ccccc1

Procedure:
4-Amino-3-benzoyl-2-methyl-5-phenylpyrrole (22.4 g.) is dissolved in 1400 ml. of chloroform and 160 ml. of 1N sodium hydroxide are added to the mixture. By keeping the temperature at 0°-5° C., 17.6 g. of phthalimidoacetyl chloride in 120 ml. of chloroform are added with stirring. After one hour the reaction mixture is cooled and the solid precipitated is recovered on filter and then crystallized from ethanol. Yield 27.8 g.; M.p. 288°-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17].C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:6]([C:7]([Cl:26])=[O:8])=[CH:5][C:4]=1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1c(C(=O)N2CCCC2)cc(C(=O)O)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1c(C(=O)N2CCCC2)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To 4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoic acid (785 mg), toluene (8 mL) and oxalyl chloride (0.64 mL) were added, and then the mixture was stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure and the obtained product was used for the synthesis of (d).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:5](O)=[O:6].[CH3:19][S:20]([NH2:23])(=[O:22])=[O:21].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:5]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:6]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(Oc2ccc(Cl)cc2)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)c1ccc(Oc2ccc(Cl)cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A mixture of 3-bromo-4-(4-chlorophenoxy)-benzoic acid (Preparation 29, 19 g, 58 mmol), methanesulfonamide (9.67 g, 102 mmol), EDCI (19.33 g, 101.5 mmol) and DMAP (12.34 g, 101.5 mmol) in DMF (200 mL) was stirred at room temperature for 16 hours. The reaction mixture was evaporated in vacuo, diluted with DCM (500 mL), washed with aqueous 1M HCl (3×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 50% petroleum ether in EtOAc to afford the title compound as a white solid (5.4 g).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:17][CH2:18][C@@H:19]([OH:21])[CH3:20]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:17]([CH2:18][C@@H:19]([OH:21])[CH3:20])[C:5]=32)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: C[C@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)-c1c(ccn1C[C@H](C)O)C2
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-6-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.94 g of (S)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.5 g (63%) of (S)-1-(7-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a solid with m.p. 74°.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:19]([CH2:28][CH3:29])=[N:18][C:12]=3[C:13]([NH2:17])=[N:14][C:15]=2[CH:16]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[NH2:17][C:13]1[C:12]2[N:18]=[C:19]([CH2:28][CH3:29])[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][NH:3][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:16][C:15]=2[N:14]=1
Reactant: CCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC1CCOCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cc(OCCNS(C)(=O)=O)ccc3c2n1CC1CCOCC1
Reaction time: 0.17 h
Yield: 39.9 %

Procedure:
7-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (0.450 g, 0.97 mmol; prepared as in Example 552), dichloromethane (10 mL), and triethylamine (0.418 mL, 3.00 mmol) were combined and then stirred for 10 minutes. Methanesulfonyl chloride (0.075 mL, 0.97 mmol) was added and the reaction was stirred for an additional 16 hours. The reaction mixture was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-20% CMA in chloroform) followed by recrystallization from acetonitrile to provide 0.173 g of N-(2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)methanesulfonamide as white needles.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[C:5]([N:12]([CH3:14])[CH3:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Br[CH:18]([CH3:33])[CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].C(N(CC)CC)C>CC(C)=O>[CH3:14][N:12]([CH3:13])[C:5]1[C:4]([O:15][CH3:16])=[CH:3][C:2]([NH:1][CH:18]([CH3:33])[CH2:19][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: COc1cc(N)c2ncccc2c1N(C)C
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2ncccc2c1N(C)C
Reaction time: 2 h

Procedure:
A stirred mixture of 17.2 g (0.033 mole) of 8-amino-5-dimethylamino-6-methoxyquinoline and 9.8 g (0.033 mole) of 4-bromo-1-phthalimidopentane was maintained at 145° while 5 ml of triethylamine was added dropwise. Addition of 9.8 g of 4-bromo-1-phthalimidopentane and 5 ml of triethylamine was repeated three more times, at the same temperature (145°) at 2 hr intervals. The mixture was allowed to cool, diluted with acetone and filtered. The filtrate was concentrated to a brown oil which was diluted with ether, washed with 30% KOH and extracted with chloroform. The extract was passed through a silica column and the eluate was concentrated, dissolved in ether, treated with Darco and slowly evaporated to give yellow crystals which, after washing with petroleum ether (bp 20°-40°) weighed 9.5 g and melted at 103°-105°.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]>CC(C)=O>[I:1][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: [I-]
Reactant: O=C(CCCCl)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CCCI)c1ccccc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
Sodium iodide (1.64 g, 10.95 mmol, 2 equiv) was added to a solution of 4-chloro-1-phenylbutan-1-one (1 g, 5.475 mmol, 1 equiv) in acetone. The reaction mixture was refluxed for 16 h. After cooling to ambient temperature, it was evaporated under reduced pressure to remove all the acetone. The residue was worked up using ethyl acetate and sodium bisulfite, followed by a wash with brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.4, 5%-30% ethyl acetate in hexanes) to afford the title compound as white solid (880 mg, 59%). The bottle containing the compound was wrapped in aluminium foil to stored in the freezer to avoid further darkening of the mixture; 1H NMR (400 MHz, DMSO-d6): δ 2.06-2.16 (m, 2H); 3.14 (t, 2H, J=3.2 and 4 Hz); 3.34 (t, 2H, J=6.8 and 7.2 Hz); 7.51-7.55 (m, 2H); 7.62-7.67 (m, 2H); 7.95-7.98 (m, 2H); MS for C10H11IO m/z 274.99 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:22][O:23]C2CCCCO2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH:30]1([B-](F)(F)F)[CH2:32][CH2:31]1.[K+]>>[CH:30]1([C:2]2[CH:10]=[C:9]([CH3:11])[C:8]3[N:7]([S:12]([C:15]4[CH:16]=[CH:17][C:18]([CH3:19])=[CH:20][CH:21]=4)(=[O:13])=[O:14])[CH:6]=[CH:5][C:4]=3[C:3]=2[CH:22]=[O:23])[CH2:32][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(Cl)cc(C)c32)cc1
Reactant: F[B-](F)(F)C1CC1
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C4CC4)cc(C)c32)cc1

Procedure:
The title compound was synthesized starting from 5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole as described in Example 48-A to 48-C using potassium cyclopropyltrifluoroborate in place of potassium ethylrifluoroborate in Example 48-A. MS (ESI+) m/z 354.2 (M+H).
Reaction SMILES: [O-2].[Ca+2:2].[O:3]=[C:4]([OH:15])[C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6].[B:16]([OH:19])([OH:18])[OH:17]>O>[B:16]1([OH:17])[O:10][CH:9]([CH:7]([OH:8])[CH:5]([OH:6])[C:4]([O-:15])=[O:3])[CH:11]([CH2:13][OH:14])[O:12]1.[B:16]1([OH:19])[O:18][CH:9]([CH:7]([OH:8])[CH:5]([OH:6])[C:4]([O-:15])=[O:3])[CH:11]([CH2:13][OH:14])[O:17]1.[Ca+2:2]
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: OB(O)O
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Product: O=C([O-])C(O)C(O)C1OB(O)OC1CO
Yield: 40 %

Procedure:
28 grams of calcium oxide were added to water to form a thick slurry. This slurry was slowly added with stirring to 392 grams of a 50% aqueous solution of technical grade gluconic acid. After all of the slurry was added the resultant mixture was cooled and 61.8 grams of technical grade boric acid added. The mixture was stirred until a dark brown solution was obtained and then adjusted by water addition to provide a 40% solids solution.