Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:29])[CH2:18][CH:19]2[CH2:27]Cl)[C:14](=[CH2:30])[CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]>C1CCCCC=1.C(O)C.[Pd]>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:29])[C@@H:18]4[CH2:27][C@@H:19]42)[C@@H:14]([CH3:30])[CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: C=C1C[C@H]2[C@@H]3CC[C@](OC(C)=O)(C(C)=O)[C@@]3(C)CC[C@@H]2[C@]2(C)C1=CC(=O)CC2CCl
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of 533 mg of 10% Pd/C in 31 ml of cyclohexene and 46 ml of ethanol is stirred for one hour at 80° C. bath temperature. To this mixture is added 7.5 g of 17-acetoxy-1-chloromethyl-6-methylene-4-pregnene-3,20-dione and the mixture is further stirred for 18 hours at 80° C. Subsequently the catalyst is suctioned off, washed with warm ethanol, and the filtrate is combined with 7 ml of concentrated hydrochloric acid. The mixture is concentrated to one-third of the reaction volume and poured on an ice water-sodium chloride solution. After the usual working-up step, the crude product is purified on 700 g of silica gel with a hexane-ethyl acetate gradient. Yield: 4.3 g of 17α-acetoxy-6α-methyl-1α,2α-methylene-4-pregnene-3,20-dione, mp 198°-200° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.CN(C)C=O.O.[C:15]1([CH3:23])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1>>[CH3:23][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1
Reactant: ClCc1c[nH]cn1
Reactant: Cc1cc(C)cc(C)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(Cc2c[nH]cn2)c(C)c1

Procedure:
3.0 g of 4-chloromethylimidazole hydrochloride are suspended in 20 ml of mesitylene. 5 ml of dimethylformamide are added and the reaction mixture is refluxed for 12 hours, then cooled. 30 ml of water are added, the layers are separated, and the aqueous phase is washed with chloroform. The aqueous solution is then made alkaline with sodium carbonate solution and extracted with chloroform. The combined chloroform extracts are washed with water and evaporated to dryness. The residue, which is crude 4-(2',4',6'-trimethylbenzyl)imidazole, is converted to the hydrochloride by treatment with concentrated hydrochloric acid. The hydrochloride salt melts at 166°-169° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH2:12][CH2:13][CH2:14][OH:15])[CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:15][CH2:14][CH2:13][CH2:12][N:7]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:16])[CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:27])=[O:26]
Reactant: CC(C)CN(CCCO)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
tert-Butyl(3-hydroxypropyl)(isobutyl)carbamate (0.73 g, 3.15), triethylamine (0.64 g, 6.30 mmol) and CH2Cl2 (30 mL) were added to a round-bottom flask. To the solution was added methanesulfonyl chloride (0.54 g, 4.72 mmol) and the reaction mixture was stirred for 5 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (hexanes/EtOAC) to afford the desired product (0.63 g, 64%) as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH3:11]>ClCCl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(CO)ccc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C=O)ccc1F
Yield: 90 %

Procedure:
(4-Fluoro-3-methoxyphenyl)methanol (5.00 g, 0.03 mol) and manganese dioxide (33.4 g, 0.38 mol) were stirred in dichloromethane (100 ml) under an atmosphere of nitrogen, at gentle reflux for 16 hours. The cooled reaction mixture was then filtered through arbacel and concentrated in vacuo to give the title compound as a white solid (4.18 g, 0.027 mol, 85%). 1H NMR (CDCl3, 400 MHz) δ: 3.96 (s, 3H), 7.23 (d, 1H), 7.43 (m, 1H), 7.50 (d, 1H) 9.91 (s, 1H). Mpt: 61-63° C. Analysis found C, 62.18; H, 4.54%. C8H7FO2 requires C, 62.34; H, 4.58%.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:17]([C:24]1[O:28][C:27]([C:29](=[N:35]O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH2:33]([O:32][C:30](=[O:31])[CH:29]([C:27]1[O:28][C:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:25][CH:26]=1)[NH:35][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:34]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(=NO)c1ccc(Cc2ccccc2)o1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(NC(=O)C(CSC(C)=O)Cc1ccccc1)c1ccc(Cc2ccccc2)o1

Procedure:
The title compound was prepared from 2-(acetylthiomethyl)-3-phenylpropionic acid (US 4329495) and ethyl (5-benzyl)furan-2-yl-2-hydroxyiminoacetate (Description 42) by the procedure of Description 40. νmax (CHCl3) 3428, 1741 and 1683cm-1. m/z 479 M+). [Found (HRMS): m/z 479.1768. Calc. for C27H29NO5S; 479.1766].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([OH:11])=O)(=[O:6])=[O:5].S(Cl)([Cl:14])=O>>[Cl:1][CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([Cl:14])=[O:11])(=[O:6])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCS(=O)(=O)CCCl
Product: O=C(Cl)CCS(=O)(=O)CCCl

Procedure:
20 g of 3-(2-chloroethylsulphonyl)-propionic acid was mixed with 70 ml thionyl chloride and the mixture refluxed for 2 hours. Excess thionyl chloride was distilled off under reduced pressure and the product recrystallised from benzene/petrol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][C:17](C)([O-])[CH3:18].[K+].C(Br)C=C>C1COCC1>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH:17]=[CH2:16]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCOc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Yield: 65 %

Procedure:
The crude phenol 2i [4-(4-hydroxyphenyl)-benzonitrile] was dissolved in 250 mL of anh THF and added to a 500-mL 3-neck round-bottom flask and stirred at 25° C. Potassium tert-butoxide (0. 89 g, 8 mmol) was added to the solution, which turned yellow. Allyl bromide was added in excess (5.0 mL, 40 mmol) and the mixture was refluxed overnight. The THF and allyl bromide were removed by rotoevaporation. The resultant sludge was extracted 5 times with mL of hexane. This material was purified chromatographically (200 mesh Kieselgel 60, 2 % EtOAc 98% in hexane) to afford 1.0 g of white crystalline material (65%): mp 68°-69° C.; IR 3083, 3013, 2884, 2225, 1604, 1492, 1455, 1291, 1249, 1180, 995, 940, 824, 533 cm-1 ; 1H NMR δδ 7.6-7.8 (m, 4H), 7.4-7.5 (d, 2H), 6.9-7.0 (d, 2 H), 5.9-6.0 (m, 1 H), 5.2-5.4 (m, 2 H), 4.5 (d, 2 H); MS m/e 235 (M+), 220, 207, 166. Anal. Calcd for C14H11NO: C, 81.68; H, 5.56. Found C, 81.56; H, 5.68.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]2[CH2:17][CH:12]1[CH2:13][C:14]2([OH:29])[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][NH:22][C:21]2=[O:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]2[CH2:17][CH:12]1[CH2:13][C:14]2([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][N:22]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:21]2=[O:28])[OH:29])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(OCc1ccccc1)N1CC2CC1CC2(O)c1ccc2nc[nH]c(=O)c2c1
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2ccc(C3(O)CC4CC3CN4C(=O)OCc3ccccc3)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a mixture of 12 (10 g, 25.6 mmol) in dimethylforamide (100 mL) was added BrCH2CO2CH2CH3 (5.55 g, 33.21 mmol). The mixture was stirred overnight at room temperature. The reaction was quenched by water and extracted with ethyl acetate. The combined organic layer was washed by water for 5 times and dried over sodium sulfate, and then concentrated in vacuo to give the product 13 (9.7 g, 80%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH:15]=[N:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F-].C[N+](C)(C)C.[F:29][C:30]([Si](C)(C)C)([F:32])[F:31]>O1CCCC1>[CH:1]1([CH2:4][C:5]2([CH:15]([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:30]([F:32])([F:31])[F:29])[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)S(=O)N=CC1(CC2CC2)CCC2(CC1)OCCO2
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(C(F)(F)F)C1(CC2CC2)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
A solution of 2-methyl-propane-2-sulfinic acid 1-(8-cyclopropylmethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-methylideneamide (19, 1.00 g, 3.05 mmol) in tetrahydrofuran was cooled to −40° C. and was treated sequentially with tetramethylammonium fluoride (313 mg, 3.36 mmol, 1.1 eq.) and (trifluoromethyl)trimethylsilane (587 μL, 3.97 mmol, 1.3 eq.). The mixture was stirred for 2 h at 0° C. before being quenched by addition of saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo to give 960 mg of the title compound. Rt=1.63 min (Method B). Detected mass: 398.3 (M+H+).
Reaction SMILES: [H-].[Na+:2].[CH3:3][N:4]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5]1.Cl[C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C([O-])(=O)C.[Na+]>CS(C)=O>[CH3:3][N:4]1[CH2:8][CH2:7][CH:6]([O:9][C:11]2[C:12]([C:13]([O-:15])=[O:14])=[CH:16][CH:17]=[CH:18][N:19]=2)[CH2:5]1.[Na+:2]
Reactant: CN1CCC(O)C1
Reactant: O=C(O)c1cccnc1Cl
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCC(Oc2ncccc2C(=O)[O-])C1
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 6.4 g (0.13 mole) of 50% sodium hydride (mineral oil) in 50 ml of dimethylsulfoxide was added dropwise 6.4 g (0.063 mole) of 1-methyl-3-pyrrolidinol. During addition, the temperature rose from 25° C. to 31° C. After 10 minutes, a solution of 10 g (0.063 mole) of 2-chloronicotinic acid in 50 ml of dimethylsulfoxide was added dropwise causing the temperature to rise. When the temperature reached 55° C., it was maintained there by the intermittent use of an ice bath until addition was complete. The mixture was then heated to 55°-60° C. for 1.5 hr., cooled and filtered. The filter cake was suspended in 100 ml of ethyl acetate and filtered. The solid was recrystallized from ethyl acetatemethanol. Yield of product was 5 g., dec. 240° C. The NMR analysis showed that the compound contained 1/3 mole of sodium acetate as impurity.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][CH:2]1[N:7]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: Clc1ccc2ccccc2n1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc2ccccc2n1
Temperature: 130 °C

Procedure:
A reaction mixture of 1 g (4.99 mmol) of tert.butyl 3-methyl-piperazine-1-carboxylate, 0.588 g (3.6 mmol) of 2-chloroquinoline and 0.498 g (3.6 mmol) of potassium carbonate is heated to 130° C. for three hours. Then the solvent is distilled off. The residue is purified by column chromatography on silica gel (eluant: dichloromethane/ethanol/ammonia=30:1).
Reaction SMILES: F[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1.C(OCC)(=[O:26])C>O=[Mn]=O>[CH:2]([C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1)=[O:26]
Reactant: CCOC(C)=O
Reactant: NS(=O)(=O)c1ccc(-n2nc(CF)cc2-c2ccccc2)cc1
Agent: O=[Mn]=O
Product: NS(=O)(=O)c1ccc(-n2nc(C=O)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the alcohol prepared in Example 131, Step 3 (1.1 g, 3.3 mmol) in ethyl acetate (20 mL) was added MnO2 (5 g, 60 mmol) and the mixture stirred at room temperature overnight. The mixture was filtered through Celite and the solution was concentrated to provide the crude aldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:32])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:15][CH2:14][C:13]([F:32])([F:12])[CH2:18][CH2:17]1)[C:22]1[CH:27]=[N:26][C:25]([C:28]([F:29])([F:30])[F:31])=[N:24][CH:23]=1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=466.1, tR (minutes, Method F)=2.67
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13](OS(C(F)(F)F)(=O)=O)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:29][CH2:30][C:31]1[O:35][C:34](=[O:36])[NH:33][N:32]=1.C(NC(C)C)(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([NH:29][CH2:30][C:31]3[O:35][C:34](=[O:36])[NH:33][N:32]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NCc1n[nH]c(=O)o1
Reactant: COc1ccc(-c2cc3ncccc3c(OS(=O)(=O)C(F)(F)F)n2)cc1OC
Solvent: CC(=O)N(C)C
Solvent: CC(C)NC(C)C
Product: COc1ccc(-c2cc3ncccc3c(NCc3n[nH]c(=O)o3)n2)cc1OC
Temperature: 70 °C

Procedure:
97 mg Trifluoromethanesulfonic acid 7-(3,4-dimethoxy-phenyl)-[1,6]-naphthyridine-5-yl ester (6.2), 30 mg 5-aminomethyl-3H-[1,3,4]oxadiazole-2-one (2.33) and 0.132 mL N,N-diisopropylamine were placed in dimethylacetamide at ambient temperature. The reaction was heated to 70° C. overnight. After this time the reaction was cooled to ambient temperature and additional 0.132 mL N,N-diisopropylamine were added. The reaction was heated to 90° C. for 6 h. After this time, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic phase was separated and the aqueous phase was extracted with additional ethyl acetate (×3) and the combined organic fractions were dried over sodium sulfate, filtered and the solvent was concentrated from the filtrate under reduced pressure. Purification by and then by silica gel chromatography (ethyl acetate/methanol: 100:0 to 95:5) provided the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]2[C:17]3[CH:16]=[CH:15][C:14]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:26])[C:9]=2[N:27]=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>N1C=CC=CC=1>[NH2:26][C:10]1[C:9]2[N:27]=[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:44]([NH:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:45])[N:7]([CH2:28][CH2:29][O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:8]=2[C:17]2[CH:16]=[CH:15][C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc(CCCCNC(=O)Nc1ccccc1)n2CCOc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, a mixture of 2-(4-aminobutyl)-7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.40 g, 0.83 mmol) and pyridine (10 mL) was cooled to 0° C., and phenyl isocyanate (91 μL, 0.84 mmol) was added. The reaction was stirred for one hour and additional phenyl isocyanate (10 μL) was added. The reaction was stirred for one hour and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 95:5-chloroform:methanol), recrystallized from toluene, and dried in a vacuum oven to provide 150 mg of TV-{4-[4-amino-7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-2-yl]butyl}-N′-phenylurea as a white crystalline solid, mp 186.3-186.9° C.
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[CH2:26]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])/[CH:27]=[CH:28]/[C:29]#[CH:30]>C(#N)C.C(N(CC)CC)C.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.[Cu]I>[NH2:25][C:4]1[C:3]([C:30]#[C:29]/[CH:28]=[CH:27]/[CH2:26][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[N:8][CH:7]=[N:6][C:5]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: C#C/C=C/CNC(=O)OC(C)(C)C
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#C/C=C/CNC(=O)OC(C)(C)C)c3N)cc2C)cn1
Yield: 45.9 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl (2E)-2-penten-4-yn-1-ylcarbamate (194 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and copper(I) iodide (10.2 mg) were sequentially added. The title compound (199 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:21](=[O:25])[CH2:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 98.4 %

Procedure:
To a 3-necked RBF (round bottomed flask) is added dichloromethane (2.4 L), (S)-4-benzyl-2-oxazolidinone (200 g, 1.13 moles) and N,N-Dimethyl-4-pyridinamine, (13.6 g; 111.32 mmoles). The flask is cooled in an ice water bath and triethylamine (472 mL; 3.39 moles) is added dropwise at 0° C. To the resulting solution is then added dropwise butanoyl chloride (152.2 mL; 1.46 moles) over 3 h, while keeping the temperature below 5° C. The reaction is then filtered and the filtrate is washed with 1M HCl (aq.) (500 ml×1) and saturated NaHCO3 (500 ml×1). The organic phase is dried over Na2SO4, filtered, and concentrated to afford the title compound (275 g, MS:[M+H]+=248.1 m/z).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:13][C@H:14]1[CH:18]=[CH:17][C:16](=[O:19])[N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].F.[K]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:18]2[CH2:17][C:16](=[O:19])[N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:14]2[CH3:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: C[C@H]1C=CC(=O)N1C(=O)OC(C)(C)C
Agent: F
Agent: [K]
Product: COc1ccc([C@@H]2CC(=O)N(C(=O)OC(C)(C)C)[C@H]2C)cc1Cl
Temperature: 60 °C
Yield: 49.3 %

Procedure:
To a 100 mL RBF were added (3-chloro-4-methoxyphenyl)boronic acid (1.89 g, 10.14 mmol), (S)-tert-butyl 2-methyl-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (1 g, 5.07 mmol), hydroxy(cyclooctadiene)rhodiumRhodium(I) dimer (0.116 g, 0.254 mmol), potassium hydrogen fluoride (1.58 g, 20.28 mmol). The mixture was degassed and filled back with N2. Dioxane (45 mL) and water (5 mL) were then added. The mixture was degassed again and filled with N2. The reaction mixture was heated at 60° C. overnight. It was diluted with EtOAc (200 mL), washed with water, brine. Organic layer was dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography, eluted with 30% EtOAc/Hexane to give (2S,3S)-tert-butyl 3-(3-chloro-4-methoxyphenyl)-2-methyl-5-oxopyrrolidine-1-carboxylate (intermediate J1, 0.85 g) as white crystalline solid. 1H NMR (500 MHz, CDCl3): δ 7.20 (s, 1H), 7.05 (d, 1H), 6.87 (d, 1H), 4.08 (m, 1H), 3.86 (s, 3H), 2.95 (m, 2H), 2.53 (m, 1H), 1.52 (s, 9H), 1.41 (d, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C@H:15]2[CH2:20][CH2:19][C@@H:18]([OH:21])[CH2:17][CH2:16]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[Li+].O>CO>[OH:21][C@@H:18]1[CH2:19][CH2:20][C@H:15]([N:9]2[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cnn([C@H]2CC[C@@H](O)CC2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn([C@H]2CC[C@@H](O)CC2)c1C(F)(F)F
Temperature: 80 °C

Procedure:
cis-1-(4-Hydroxy-cyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (94.7 mg, 0.309 mmol) was dissolved in methanol (0.5 mL). Lithium hydroxide (10.3 mg, 0.430 mmol) and water (0.5 mL) were added and the mixture was heated at 80° C. for 1 hour. After cooling to room temperature, the methanol was removed in vacuo. Tetrahydrofuran was added and removed in vacuo to insure complete removal of methanol. The residue was diluted with water and acidified with 6N HCl (75 μL; pH 1.5-2). The solid which precipitated out of solution was collected by filtration, washed with water and dried under high vacuum at 50° C. to give cis-1-(4-hydroxy-cyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (70 mg; 81%). Mass spectrum: m/z: 279.1 (M+H).