Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[C:38]([CH2:39][CH3:40])=[N:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19][C@:18]2([C:43]([OH:45])=O)[CH2:42][C@H:17]2[CH2:16][C:15]([F:47])([F:46])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:64]1([S:67]([NH2:70])(=[O:69])=[O:68])[CH2:66][CH2:65]1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[CH:64]1([S:67]([NH:70][C:43]([C@@:18]23[CH2:42][C@H:17]2[CH2:16][C:15]([F:47])([F:46])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]4[C:38]([CH2:39][CH3:40])=[N:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19]3)=[O:45])(=[O:69])=[O:68])[CH2:66][CH2:65]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CCc1nc2ccccc2nc1O[C@@H]1C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(Cl)Cl
Product: CCc1nc2ccccc2nc1O[C@@H]1C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Temperature: 40 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To (2R,6S ,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-2-(3-ethylquinoxalin-2-yloxy)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (Example 7k, 26.2 mg, 0.040 mmol) was added sieves (4 A) and dichloroethane (397 μl). To this mixture was added carbonyldiimidazole (13.5 mg, 0.083 mmol), and the reaction mixture was stirred at 40° C. for 2 hr. The reaction mixture was then cooled to room temperature and cyclopropanesulfonamide (12.4 mg, 0.103 mmol) was added followed by DBU (15 μl, 0.100 mmol). The reaction mixture was stirred at room temperature for 16 h, diluted with dichloromethane and cooled to 0° C. This mixture was neutralized with HCl (4 N in dioxane, 67 μl), and the mixture was filtered to remove sieves. The eluant was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (CH3CN/H2O (0.1% TFA) gradient =45/55-85/15) to provide tert-butyl (2R,6S ,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-2-(3-ethylquinoxalin-2-yloxy)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (25.8 mg, 85% yield) as a light yellow solid. MS (ESI): m/z=763.0 [M+H], 761.3 [M−H]. Example 7 provided an IC50 of between 0.5 and 1.0 nM in a 1a enzyme assay; an IC50 of between 0.1 and 0.5 nM in a 1b enzyme assay; a HLM stability value of >100 μl/min/mg; an EC50 of between 2.0 and 5.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of between 1.0 and 2.0 nM in a replicon cell line assay in a 1b-con1 background.
Reaction SMILES: C[C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9](CCOC3C=CC=CC=3)[C:8]2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.CN1C=CC=C1CN>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:9][CH2:10][C:11]4[N:7]([CH3:8])[CH:5]=[CH:6][CH:2]=4)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: Cn1cccc1CN
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccn1C
Yield: 26 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1-methyl-1H-pyrrol-2-yl)methanamine, the title compound was obtained as a colorless solid in 26% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.99 (m, 2H), 6.61 (s, 1H), 6.13-6.03 (m, 3H), 5.71 (t, J=4.6 Hz, 1H), 4.55 (d, J=4.6 Hz, 2H), 4.42 (s, 2H), 3.83-3.75 (m, 2H), 3.61 (s, 3H), 3.47-3.39 (m, 2H), 2.48 (s, 3H): MS (ES+) m/z 427.2 (M+1).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:10][CH2:11][CH2:12][C:13]1[C:14]([Cl:20])=[N:15][CH:16]=[N:17][C:18]=1[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:21][C:22]([OH:24])=[O:23]>>[CH2:3]([O:10][CH2:11][CH2:12][C:13]1[C:18]([CH2:19][Br:1])=[N:17][CH:16]=[N:15][C:14]=1[Cl:20])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[Br:1][CH2:19][C:18]1[C:13]([CH2:12][CH2:11][O:23][C:22](=[O:24])[CH3:21])=[C:14]([Cl:20])[N:15]=[CH:16][N:17]=1
Reactant: CC(=O)O
Reactant: Cc1ncnc(Cl)c1CCOCc1ccccc1
Reactant: BrBr
Product: CC(=O)OCCc1c(Cl)ncnc1CBr
Product: Clc1ncnc(CBr)c1CCOCc1ccccc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Br2 (1.4 g, 8 mmol) is added drop wise to a stirred solution of 5-(2-benzyloxy-ethyl)-4-chloro-6-methyl-pyrimidine (2.1 g, 8 mmol) in HOAc (20 ml) at 85° C. After addition, the mixture is stirred at 85° C. for an additional 1 hour. The solvent is removed in vacuo and EtOAc (25 ml) and NaHCO3 (25 ml) are added to the residue. The layers are separated and the organic layer is washed with Na2S2O3 solution (sat. 15 ml) followed by brine (20 ml). The organic phase is dried (Na2SO4) and solvent evaporated. The resulting yellow oil is purified by flash column (EtOAc:hexane=6:1) to afford 5-(2-benzyloxy-ethyl)-4-bromomethyl-6-chloro-pyrimidine as a light yellow solid and acetic acid 2-(4-bromomethyl-6-chloro-pyrimidin-5-yl)-ethyl ester (162).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[S:10].[C:11]([NH:19][NH2:20])(=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:19][N:20]=[C:9]1[SH:10]
Reactant: NNC(=O)c1ccncc1
Reactant: S=C=Nc1ccccc1Cl
Solvent: CC#N
Product: Sc1nnc(-c2ccncc2)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
A mixture of 1-chloro-2-isothiocyanatobenzene 1 (3 g, 17.68 mmol) and isonicotinohydrazide 2 (2.43 g, 17.68 mmol) in acetonitrile was stirred at ambient temperature for 18 hours, concentrated to dryness, and 100 mL of 10% K2CO3 (aq.) was added. The resulting mixture was stirred under reflux for 6 hours. The clear solution was cooled to ambient temperature, washed with ether and acidified with 1N HCl. The solid was collected, washed with H2O and ether, and dried to afford compound 4 (4.3 g). Yield: 86%.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.O=[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][C:16]#[N:17].[NH2:24][C:25]([CH:29]([F:31])[F:30])=[CH:26][C:27]#[N:28]>C(O)CCCC.C(#N)C>[F:30][CH:29]([F:31])[C:25]1[NH:24][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:15]([C:16]#[N:17])[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:26]=1[C:27]#[N:28]
Reactant: N#CC=C(N)C(F)F
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Reactant: N#CCC(=O)c1ccccc1
Solvent: CC#N
Solvent: CCCCCO
Product: Cc1n[nH]c2ccc(C3C(C#N)=C(c4ccccc4)NC(C(F)F)=C3C#N)cc12
Temperature: 105 °C

Procedure:
A mixture of 200 mg (1.25 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A), 217 mg (1.50 mmol) 3-oxo-3-phenylpropanenitrile and 147 mg (1.25 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 1-pentanol (1.2 ml) containing powdered 4 Å molecular sieve was heated to 105° C. overnight. After cooling, the reaction mixture was diluted with acetonitrile and directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) followed by chromatography on silica gel (eluent: toluene/dichloromethane/methanol 10:5:1 v/v) to afford 93 mg (19% of th.) of the racemic title compound.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]2([CH2:18][CH2:19][N:20]3[CH:25]4[CH2:26][CH2:27][CH:21]3[CH2:22][CH:23]([N:28]3[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]3[CH3:37])[CH2:24]4)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)[CH3:4].C(N(CC)CC)C.[Cl:45][C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][C:47]=1[S:55](=[O:58])(=[O:57])[NH2:56].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Cl:45][C:46]1[CH:54]=[CH:53][C:49]([C:50]([N:15]2[CH2:16][CH2:17][C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:3][CH3:4])[CH:7]=3)([CH2:18][CH2:19][N:20]3[C@H:21]4[CH2:27][CH2:26][C@@H:25]3[CH2:24][CH:23]([N:28]3[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[C:29]3[CH3:37])[CH2:22]4)[CH2:13][CH2:14]2)=[O:51])=[CH:48][C:47]=1[S:55]([NH2:56])(=[O:58])=[O:57]
Reactant: CCOc1cccc(C2(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)CCNCC2)c1
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cccc(C2(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)CCN(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A mixture of 1-(8-{2-[4-(3-ethoxyphenyl) piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.40 g, 0.78 mmol), triethylamine (0.35 mL, 2.5 mmol) and 4-chloro-3-sulfamoylbenzoic acid (184 mg, 0.78 mmol) in dimethylformamide (2.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (327 mg, 0.86 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting precipitate was collected, washed with saturated sodium bicarbonate solution and water, dried and purified by chromatography on silica gel eluting with a chloroform:methanol:ammonium hydroxide 400:15:1 to 200:15:1 gradient to give 2-chloro-5-[(4-(3-ethoxy phenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)carbonyl]benzenesulfonamide as a solid (0.34 g, 62%). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.67 (m, 1H), 7.59 (m, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.29 (m, 1H), 7.17 (m, 2H), 6.93-6.98 (m, 2H), 6.81 (m, 1H), 4.74 (m, 1H), 4.17 (m, 1H), 4.04 (m, 2H), 3.54 (m, 1H), 3.30 (m, 4H), 2.52 (s, 3H), 2.40-2.48 (m, 4H), 2.27 (m, 1H), 2.14 (m, 1H), 1.83-2.04 (m, 10H), 1.70 (m, 2H), 1.40 (t, 3H). HRMS C37H44ClN5O4S m/z 690.2881 (M+H)Cal., 690.2901 (M+H)Obs..
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][NH:22][C:21](=[O:25])[N:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl.Cl[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][N:22]([CH2:32][C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[C:21](=[O:25])[N:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:27])([F:29])[F:28]
Reactant: N#Cc1cc(CNc2cc[nH]c(=O)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: ClCc1cccnc1
Agent: Cl
Product: N#Cc1cc(CNc2ccn(Cc3cccnc3)c(=O)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared with a procedure similar to that described for E1 starting from 2-{[4-Chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(2-oxo-1,2-dihydro-4-pyrimidinyl)amino]methyl}benzonitrile and 3-(chloromethyl)pyridine hydrochloride. LC-MS (ESI): m/z 512 [M+H]+; 3.70 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][CH:10]([CH2:14][CH3:15])[C:11](O)=O>O>[Cl:9][CH:10]([C:11]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]=1)[CH2:14][CH3:15]
Reactant: Nc1cccnc1N
Reactant: CCC(Cl)C(=O)O
Solvent: O
Product: CCC(Cl)c1nc2cccnc2[nH]1
Temperature: 80 °C

Procedure:
5.0 g of 2,3-diaminopyridine in 200 g of polyphosphoric acid are heated at 120° C. for 0.5 h. The solution is cooled to 80° C. and 5.7 ml of 2-chlorobutyric acid are added. Thereafter, the reaction mixture is heated to 130° C. for 22 h. After cooling, the polyphosphoric acid is hydrolysed with water, the mixture is filtered using charcoal and celite and the pH value of the filtrate is adjusted to pH 4 using 9 M aqueous sodium hydroxide solution. The mixture is extracted three times each with 200 ml of ethyl acetate, the combined organic phases are dried using sodium sulfate, concentrated and the residue is purified by chromatography on silica gel (eluent: toluene/ethyl acetate 1:1) to give 5.19 g of the title compound as a colorless, amorpheous solid. M.p. 137° C. TLC: Rf=0.50 (dichloromethane/methanol 10:1).
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.O>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([CH:6]2[CH2:7][CH2:8][C:3]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:1]#[N:2])[CH2:4][CH2:5]2)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: N#CC1(c2ccccc2)CCC(N2CCN(Cc3ccccc3)CC2)CC1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
35.0 g of 4-cyano-4-phenylcyclohexanone (0.176 mol), (prepared as disclosed in J. Amer. Chem. Soc. 74, (1972) 773) were dissolved with 31 g of 1-benzylpiperazine (0.176 mol) and 21 g of acetic acid in 200 ml of ethanol and, at room temperature, a solution of 12.5 g of sodium cyanoborohydride (0.19 mol) was slowly added dropwise. The mixture was stirred overnight, and then water was added and the mixture was extracted with dichloromethane. Drying and removal of the solvent by distillation resulted in a residue of 46.6 g (76%) of oil.
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[C:4]2[C:13]3[CH:12]=[C:11]([O:14][CH3:15])[C:10]([C:16]4[C:17]([CH3:22])=[N:18][O:19][C:20]=4[CH3:21])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:23]=1.[CH2:32]([CH2:34][NH2:35])[OH:33].O>CN1C(=O)CCC1>[CH3:22][C:17]1[C:16]([C:10]2[C:11]([O:14][CH3:15])=[CH:12][C:13]3[C:4]4[N:3]([C@@H:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH3:25])[C:2]([NH:35][CH2:34][CH2:32][OH:33])=[N:23][C:5]=4[CH:6]=[N:7][C:8]=3[CH:9]=2)=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(Cl)n([C@H](C)c3ccccc3)c12
Reactant: NCCO
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(NCCO)n([C@H](C)c3ccccc3)c12
Temperature: 150 °C
Yield: 53 %

Procedure:
2-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinoline (for a preparation see Intermediate 12) (30 mg, 0.035 mmol) was dissolved in NMP (0.5 ml), ethanolamine (30 mg) was added and the mixture was heated at 150° C. for 30 min, then cooled, added to water (10 ml) and extracted with EtOAc (10 ml). The organic phase was washed with water (2×10 ml), dried and evaporated. The residue was dissolved in DCM (2 ml), loaded onto a 10 g silica column and eluted with 2M methanolic ammonia/DCM (0-10%). The product-containing fractions were evaporated in vacuo to give 2-({7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-yl}amino)ethanol (8.4 mg, 0.018 mmol, 53.0% yield) as a light brown glass. LCMS (formate) Rt 0.77 min, MH+ 458
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([CH2:21][CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[N:38]1[CH:43]=[CH:42][CH:41]=C[CH:39]=1.ClC(OC1C=CC=CC=1)=[O:46].C1(N)CC1>CN(C=O)C>[CH:43]1([NH:38][C:39](=[O:46])[NH:1][C:2]2[CH:36]=[CH:35][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[CH:17]=[N:18][N:19]([CH2:21][CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])[CH:20]=5)[S:15][C:8]=34)=[C:4]([F:37])[CH:3]=2)[CH2:41][CH2:42]1
Reactant: COCCN(CCn1cc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cn1)C(=O)OC(C)(C)C
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: NC1CC1
Solvent: CN(C)C=O
Product: COCCN(CCn1cc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cn1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
To a stirred solution of tert-butyl 2-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethyl(2-methoxyethyl)carbamate (245, 1.22 g, 2.312 mmol) and pyridine (374 μL, 4.62 mmol) in DMF (30 mL) at 0° C. was added phenyl chloroformate (348 μl, 2.77 mmol) and the reaction mixture was stirred for 30 min. Cyclopropylamine (407 μl, 5.78 mmol) was added at 0° C. and the reaction mixture was heated at 60° C. for an additional 30 min. After cooling to RT, the reaction mixture was quenched by addition of water and a saturated solution of ammonium chloride, and extracted with AcOEt. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV). The desired fractions were collected and concentrated to afford the title compound 246 (722 mg, 0.18 mmol, 61% yield) as a yellow solid. MS (m/z): 611.63 (M+H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10](Br)[CH2:11][CH2:12][CH3:13]>C1COCC1>[CH2:10]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCBr
Reactant: C1=Cc2ccccc2C1
Solvent: C1CCOC1
Product: CCCCC1C=Cc2ccccc21
Reaction time: 0.67 h

Procedure:
N-BuLi (173 mmol) was added to indene (173 mmol) in THF (70 mL) at ambient temperature using an oil bath as a heat sink. The reaction was stirred for 40 minutes, then added to n-butyl bromide (223 mmol) in THF (70 mL) at 0° C. The reaction was stirred overnight at ambient temperature, followed by standard aqueous workup. Evaporation of solvent followed by distillation under reduced pressure gave pure n-butylindene. n-BuLi (13.5 mmol) was added to n-butylindene (13.5 mmol) in THF (50 mL) and stirred for 1 hour. The solution was then added to ((tBu)3PN)TiCl3 (which was prepared by the reaction of TiCl4 with (tBu)3PN-TMS) slurried in toluene at −78° C. After stirring overnight at ambient temperature and the solvent was removed under vacuum. The residue was extracted into toluene, filtered and the filtrate concentrated. Addition of heptane precipitated the product that was isolated by filtration.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[N:8]2)=[CH:4][CH:3]=1.FC1C=CC(CN2C=C(C(O)=O)C=N2)=CC=1.S(Cl)([Cl:35])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]([Cl:35])=[O:13])[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cn2cc(C(=O)O)cn2)cc1
Reactant: O=S(Cl)Cl
Agent: O=C(O)c1cnn(Cc2ccc(F)cc2)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(Cn2cc(C(=O)Cl)cn2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid (0.618 g, 2.86 mmol), which had been prepared according to the protocol described for intermediate (6e), in Example 21, was stirred in toluene (20 mL) at RT and thionyl chloride (681 mg, 0.42 mL, 5.72 mmol) was added. The reaction mixture was slowly heated to 90° C. and heating continued for 3 hrs. After cooling the reaction was concentrated in vacuo. Toluene was added to the residue and concentrated in vacuo. This was repeated a further three times and the crude solid obtained was triturated using isohexane. The solids were separated by filtration washed with isohexane and dried in vacuo to afford 1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl chloride as a white solid, 0.67 g, quant.
Reaction SMILES: Cl.NC[C:4]1[CH:13]=[C:12]([OH:14])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:15])[CH:5]=1.[CH:16]([N:19](CC)C(C)C)(C)C.C1(=O)N(O[C:31](=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])C(=O)CC1>CN(C)C=O>[C:41]([O:40][C:38]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][C:31]([NH:19][CH2:16][C:13]1[C:12]([OH:14])=[C:7]([C:6]([OH:15])=[CH:5][CH:4]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:45])=[O:39])([CH3:42])([CH3:43])[CH3:44]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1c(O)cc(CN)cc1O
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)ccc(CNC(=O)CCCCCNC(=O)OC(C)(C)C)c1O
Reaction time: 4 h
Yield: 79.9 %

Procedure:
Methyl 4-aminomethyl-2,6-dihydroxybenzoate hydrochloride (1.50 grams, 6.4 mmoles) was suspended in anhydrous N,N-dimethylformamide (25 mL), and N,N-diisopropylethylamine (2.2 mL, 12.8 mmoles) was added, followed by N-tert-butoxycarbonyl-6-aminohexanoic acid succinimidyl ester (2.10 grams, 6.4 mmoles). The mixture was stirred under dry nitrogen for 4 hours, during which time all solids dissolved. The solvent was then evaporated to leave a light brown syrup, which was partitioned between ethyl acetate (70 mL) and 1M aqueous hydrochloric acid (50 mL). The layers were separated, and the ethyl acetate solution was washed with saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to an amorphous off-white solid. The solid was crystallized from ethyl acetate/hexanes, filtered, and dried in vacuo to afford 2.10 grams (80% yield) of methyl (N-tert-butoxycarbonyl-6-aminohexanoyl)aminomethyl-2,6-dihydroxybenzoate (m.p. 73°-76° C., open capillary, uncorrected).
Reaction SMILES: [C:1]([C:6]([OH:8])=[O:7])#[C:2][C:3](O)=[O:4].[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)=[S:19])[CH:13]=[CH:14][C:15]=1[Cl:16]>CO>[O:4]=[C:3]1[C:2](=[CH:1][C:6]([OH:8])=[O:7])[S:19][C:18](=[N:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[N:17]1[C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=1
Reactant: S=C(Nc1ccc(Cl)c(Cl)c1)Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C#CC(=O)O
Solvent: CO
Product: O=C(O)C=C1SC(=Nc2ccc(Cl)c(Cl)c2)N(c2ccc(Cl)c(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
A mixture of acetylenedicarboxylic acid (6.6 g, 55 mmoles) and N,N'-bis(3,4-dichlorophenyl)thiourea (20.0 g, 55 mmoles) in methanol (400 mls) is stirred at room temperature for 16 hours. The suspended solid is filtered off and rinsed with cold methanol. The solid is then rinsed repeatedly with boiling CH2Cl2 and filtered off. The combined dichloromethane filtrates are concentrated and cooled to afford the crystalline product (7.6 g), mp 221°-222° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:9]=2[N:10]=1>C(OCC)(=O)C>[CH3:16][O:15][C:11]1[C:9]2[N:10]=[C:6]([N:5]=[C:1]=[O:2])[S:7][C:8]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)Cl
Reactant: COc1cccc2sc(N)nc12
Solvent: CCOC(C)=O
Product: COc1cccc2sc(N=C=O)nc12

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-4-methoxybenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about one hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 4-methoxybenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH3:5][CH:6]([CH2:8][C:9]([CH3:11])=[O:10])[CH3:7].[CH3:12]C(C)=O>>[OH:3][C:2]1[CH:4]=[CH:7][C:6]2[C:5](=[CH:12][CH:11]=[C:9]([OH:10])[CH:8]=2)[CH:1]=1
Reactant: CC(C)=O
Reactant: CC(=O)CC(C)C
Product: Oc1ccc2cc(O)ccc2c1

Procedure:
Sixty parts by weight of acetone was added to 100 parts by weight of the oily phase containing the oxidation product obtained in Example 8, (1) to prepare an MIBK/acetone mixed oily phase which was subjected to acid cleavage by the following method to obtain 2,6-dihydroxynaphthalene.