Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(CCCC)CCCC)CCC.[Li]/[CH:15]=[CH:16]/[CH:17]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:31]([Si:35]([CH3:44])([CH3:43])[O:36][CH:37]1[CH2:41][C:40](=[O:42])[CH:39]=[CH:38]1)([CH3:34])([CH3:33])[CH3:32].[O:45]=[CH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53].[Cl-].[NH4+]>CCOCC.O1CCCC1.CCCCCC>[OH:45][CH:46]([CH:39]1[CH:38](/[CH:15]=[CH:16]/[CH:17]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:37]([O:36][Si:35]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:44])[CH3:43])[CH2:41][C:40]1=[O:42])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52](=[O:53])[O:54][CH3:55]
Reactant: COC(=O)CCCCCC=O
Reactant: [Li]/C=C/C(CCCCC)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(=O)C1
Agent: CCCCP(CCCC)CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC(/C=C/C1C(O[Si](C)(C)C(C)(C)C)CC(=O)C1C(O)CCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Cuprous chloride (229 mg; 1.2 mmoles) was weighed into a 50 ml flask, and the inside atmosphere of the flask was purged with argon. Anhydrous ether (10 ml) was added, and then 0.60 ml (2.4 mmoles) of tri-n-butylphosphine was added at room temperature, followed by stirring for 10 minutes. The mixture was then cooled to -78° C., and a solution of 1.2 mmoles of dl 1-lithio-3-(t-butyldimethylsilyloxy)-trans-octene in a mixture of anhydrous ether and anhydrous hexane was added. The mixture was stirred at -78° C. for 30 minutes, and a solution of 212 mg (1.0 mmole) of dl 4-(t-butyldimethyl-silyloxy)-2-cyclopentenone in 5 ml of anhydrous ether was added dropwise. The mixture was stirred at -78° C. for 1 hour. Then, 0.15 ml of a boron trifluoride/ether complex was added, and the mixture was stirred at -78° C. for 10 minutes, and then at -40° C. for 20 minutes. Then, 5 ml of anhydrous tetrahydrofuran was added, and a solution of 221 mg (1.4 mmoles) of methyl 7-ketoheptanoate in 5 ml of anhydrous tetrahydrofuran was added. The mixture was stirred at -40° C. for 1.5 hours. The temperature of the mixture was gradually raised to room temperature, and the product was hydrolyzed with a saturated aqueous solution of ammonium chloride and extracted with ether. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography. From the eluates resulting from elution with hexane/ethyl acetate (=9/1), two stereoisomers, dl 2-(1-hydroxy-7-keto-8-oxanonyl)-3-[3-(t-butyldimethylsilyloxy)-1-trans-octenyl]-4-(t-butyldimethylsilyloxy)cyclopentanone, were obtained in an amount of 59 mg (TLC: Rf=0.39; developing solvent hexane/ethyl acetate=4/1) and 35 mg (TLC: Rf=0.35; developing solvent hexane/ethyl acetate=4/1), respectively.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:16][NH2:17]>CCO>[CH3:16][NH:17][C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])NCc1cccnc1
Reactant: CN
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCc1cccnc1
Yield: 76.8 %

Procedure:
In 50 ml of EtoH was dissolved 2.3 g (0.01 mole) of 1-methylthio-1-(3-pyridylmethyl)amino-2-nitroethylene with heating and, then, a solution of 1:2 g (0.015 mole) of 40% aqueous methylamine in 10 ml of EtOH was added dropwise over a period of 30 minutes while refluxing. The mixture was further refluxed for 2 hours, after which it was concentrated. The crystals were collected by filtration and recrystallized from acetonitrile to give 1.6 g of the title compound as white prisms.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[CH2:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33]N)[C:28]=2[F:35])=[CH:23][CH:22]=1)[CH2:18][CH2:19][CH3:20].C(C1C=CC(B(O)O)=CC=1)CCC>>[CH2:17]([C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:28]([F:35])=[C:29]3[C:30]([C:3]4[CH2:4][CH2:5][CH2:6][C:7]5[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:8]=5[C:2]=4[NH:33]3)=[CH:31][CH:32]=2)=[CH:25][CH:26]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCc1ccc(-c2cccc(NN)c2F)cc1
Reactant: O=C(O)c1ccc2c(c1)CCCCC2=O
Agent: CCCCc1ccc(B(O)O)cc1
Agent: Cl
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2ccc(C(=O)O)cc2CCC4)cc1
Yield: 34 %

Procedure:
The title material is prepared in 34% yield by reacting 5-Oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid (J. Org. Chem. 1962, 27(1), p 70-76) and (4′-Butyl-2-fluoro-biphenyl-3-yl)-hydrazine hydrochloride (prepared as in example 69, steps 1 and 2 except using 4-n-butylphenylboronic acid as the coupling partner) in an analogous manner to example 1, step 3 except that purification is accomplished by reverse phase mass triggered HPLC: 1H NMR (Acetone-d6) δ 10.72 (bs, 1H), 8.09 (d, 1H), 7.99 (d, 1H), 7.92 (s, 1H), 7.58 (d, 2H), 7.45 (d, 1H), 7.31 (d, 2H), 7.17 (dd, 1H), 3.18 (t, 2H), 3.10-3.04 (m, 2H), 2.72 (t, 2H), 2.22-2.14 (m, 2H), 1.73-1.64 (m, 2H), 1.45-1.38 (m, 2H), 0.96 (t, 3H); LC/MS calculated for [M+H]+ C28H26FNO2: 428.2, found: 428.2.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:4]1[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(-n2cc(C)c3c(=O)[nH]c(C)nc32)c(C)c1
Product: Cc1cc(C)c(-n2cc(C)c3c(Cl)nc(C)nc32)c(C)c1
Temperature: 0 °C

Procedure:
A mixture of the compound of step C (1.030 g, 3.67 mmol) and POCl3 (3 ml) was heated at reflux for 2.5 hours and cooled. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with dilute sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give the title compound as a tan solid which was purified through silica gel to give an off-white solid. 1H NMR (CDCl3) δ 1.90(s, 6H), 2.35(s, 3H), 2.50(s, 3H), 2.65(s, 3H), 6.78(s, 1H), 7.00(s, 2H) ppm.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C@@H:3]([NH:12][C:13]1[CH:14]=[C:15]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]([O:30]CC)=[O:29])[CH:26]=3)[NH:21][CH:20]=2)[CH:16]=[N:17][CH:18]=1)[C:4](=[O:11])[NH:5][CH2:6][C:7]([F:10])([F:9])[F:8].[OH-].[Na+]>CO>[CH3:1][CH:2]([CH3:33])[C@@H:3]([NH:12][C:13]1[CH:14]=[C:15]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=3)[NH:21][CH:20]=2)[CH:16]=[N:17][CH:18]=1)[C:4](=[O:11])[NH:5][CH2:6][C:7]([F:8])([F:10])[F:9]
Reactant: CCOC(=O)c1cnc2[nH]cc(-c3cncc(N[C@@H](C(=O)NCC(F)(F)F)C(C)C)c3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@@H](Nc1cncc(-c2c[nH]c3ncc(C(=O)O)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 50 °C

Procedure:
To ethyl 3-(5-(3-methyl-1-oxo-1-(2,2,2-trifluoroethylamino)butan-2-ylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate 3-1a (0.775 g, 1.724 mmol) in methanol (18 mL) was added sodium hydroxide (5.17 ml, 5.17 mmol). The mixture was heated at 50° C. for 18 hrs. The reaction was concentrated in vacuo and aqueous washed with diethyl ether. The aqueous extract was concentrated and 1N HCl added until a precipitate forms (˜pH6). The solid was filtered to give the desired product. 0.467 g. LRMS (ESI) m/z 436.2 [(M+H)+; calcd for C20H20F3N5O3: 436.2.
Reaction SMILES: O1CCOCC1.C1COCC1.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ClCCl.[C:23]1([CH3:31])[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=1>Cl[Ti](OC(C)C)(OC(C)C)OC(C)C>[CH3:31][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([OH:30])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:25][CH:24]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1ccc(C=O)cc1
Agent: CC(C)O[Ti](Cl)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc([C@H](O)c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
1.0 mL (12 mmol) of anhydrous 1,4-dioxane was added to 0.375 mL (0.375 mmol) of an anhydrous THF solution (1.00 mol/L) of commercial phenylmagnesium bromide, and the contents were stirred for 10 minutes, and then 0.402 mL (0.325 mmol) of an anhydrous dichloromethane solution (0.80 mol/L) of chloro-tri-iso-propoxy titanium prepared in Preparation Example 1 was added thereto, and further stirred for 10 minutes. 0.25 mL (0.0125 mmol) of an anhydrous dichloromethane solution (0.050 mol/L) of (R)—H8-BINOL was added thereto and stirred at room temperature for 30 minutes. The thus-obtained solution containing a white precipitate was added dropwise to 30 mg (0.25 mmol) of a dichloromethane solution (0.5 mL) of p-tolualdehyde using a syringe over a period of 10 minutes, and stirred at room temperature for 1 hour for the reaction. Thereafter, an operation was carried out in the same manner as in Example 1 to obtain (R)-4-methylbenzhydrol. The conversion rate of the raw material was 80%, while the enantiomeric excess of the product was 94% ee. The amount of dioxane used during the reaction was 32 equivalents (64 equivalents in terms of the ether oxygen equivalent) relative to magnesium.
Reaction SMILES: [C:1](=[O:39])([O:3][CH2:4][CH:5]([NH:16][C:17](=[O:38])[CH2:18][N:19]1[C:23](=[O:24])[N:22](/[CH:25]=[CH:26]/[C:27]([F:30])([F:29])[F:28])[C:21]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[N:20]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])[NH2:2]>CO.[Pt]>[C:1](=[O:39])([O:3][CH2:4][CH:5]([NH:16][C:17](=[O:38])[CH2:18][N:19]1[C:23](=[O:24])[N:22]([CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:21]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)=[N:20]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])[NH2:2]
Reactant: NC(=O)OCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O)c1ccccc1C(F)(F)F
Agent: [Pt]
Solvent: CO
Product: NC(=O)OCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCC(F)(F)F)c1=O)c1ccccc1C(F)(F)F

Procedure:
A solution of 118 mg (0.20 mmol) of the compound from Example 143 in 20 ml of methanol was hydrogenated by means of a continuous-flow hydrogenation apparatus (H-Cube, Thales Nano, Budapest, Model HC-2-SS), equipped with a 5% Pt/C catalyst cartridge, at 45° C. with a flow rate of 1 ml/min under standard pressure. The methanol was removed on a rotary evaporator and the residue was purified by preparative HPLC [Method 10]. This gave 31 mg (26% of theory) of the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[C:5]#[N:6])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: c1c[nH]cn1
Product: N#Cc1cc(-n2ccnc2)cc(C(F)(F)F)c1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 3-fluoro-5-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH) and imidazole (Fluka, Buchs, Switzerland), with a reaction temperature of 110° C. for 24 hours.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:13][C@@H:14]([CH3:33])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=2)=[N:17]1>>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:6][CH:7]=3)=[O:12])[CH3:33])[N:17]=2)=[CH:22][C:23]=1[C:29]([F:30])([F:32])[F:31])#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Reactant: CC(C)(O)c1nc(C(=O)O)co1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1)NC(=O)c1coc(C(C)(C)O)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(2-hydroxypropan-2-yl)-oxazole-4-carboxylic acid (0.3 g, 1.75 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile (0.516 mg, 1.75 mmol). The product was purified by column chromatography. Yield 270 mg. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 1.51 (s, 6H), 4.30-4.52 (m, 3H), 5.67 (s, 1H), 7.05 (s, 1H), 7.86 (d, 1H), 8.17 (d, 2H), 8.28 (d, 2H), 8.47 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:15]([NH:17][C:18]2[S:19][C:20]([S:23][C:24]#N)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S[CH2:33][C@@H:34]([C@@H:36]([CH2:38][SH:39])O)O.CI>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:15]([NH:17][C:18]2[S:19][C:20]([S:23][CH3:24])=[CH:21][N:22]=2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[CH:26]1([N:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([C:38]3[S:39][CH:33]=[CH:34][CH:36]=3)=[O:5])[CH2:13][CH2:12]2)[C:15]([NH:17][C:18]2[S:19][C:20]([S:23][CH3:24])=[CH:21][N:22]=2)=[O:16])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: O[C@H](CS)[C@@H](O)CS
Solvent: CI
Product: CSc1cnc(NC(=O)N(C2CCCCC2)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Product: CSc1cnc(NC(=O)N(C2CCCCC2)C2CCN(C(=O)c3cccs3)CC2)s1

Procedure:
4-[1-Cyclohexyl-3-(5-methylsulfanyl-thiazol-2-yl)-ureido]-piperidine-1-carboxylic acid tert-butyl ester was prepared as described in general procedure (H) and (I) using 4-[1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-ureido]-piperidine-1-carboxylic acid tert-butyl ester, dithioerythritol and methyl iodide. Removal of the Boc group and N-acylation using thiophene-2 carboxylic acid as described in general procedure (G), steps 3 and 4 gave the title compound.
Reaction SMILES: C(C1C=CC=C(OC)C=1C[C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[C:8]([O:22][CH3:23])[C:7]=1[C:24]([O:26]C(C)(C)C)=[O:25])=O.C([Si](OCCC(OCOC)C#C)(C)C)(C)(C)C>>[CH3:23][O:22][C:8]1[C:7]([C:24]([OH:26])=[O:25])=[CH:6][C:19]2[C:18](=[O:20])[C:17]3[C:12]([C:11](=[O:21])[C:10]=2[CH:9]=1)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: COc1cccc(C=O)c1Cc1c(C(=O)OC(C)(C)C)c(OC)cc2c1C(=O)c1ccccc1C2=O
Agent: C#CC(CCO[Si](C)(C)C(C)(C)C)OCOC
Product: COc1cc2c(cc1C(=O)O)C(=O)c1ccccc1C2=O

Procedure:
Analogously to example 12, tert-butyl 1-(2′-formyl-6′-methoxybenzyl)-3-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate was reacted with tert-butyl-(3-methoxymethoxypent-4-ynyloxy)dimethylsilane. After work-up by column chromatography on silica gel (CHCl3/EA 95:5), the addition product tert-butyl 6″-(tert-butyldimethylsilanyloxy)-1″-hydroxy-4″-methoxymethoxyhex-2″-ynyl]-6′-methoxybenzyl}-3-methoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid could be obtained in the form of a yellow oil (230 mg, 0.31 mmol, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[NH:12][C:11]1=[O:19])[CH2:6][CH2:7][CH3:8])[CH3:2].[I-].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N+](C)(C)C)=[CH:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]([CH2:33][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[N:23]([CH3:22])[CH:24]=2)[C:11]1=[O:19])[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: CCCC(Cn1c(=O)[nH]c2cccnc21)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(Cn1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cccnc21)C(=O)OCC
Temperature: 60 °C
Yield: 108.7 %

Procedure:
To a solution of 2-(2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-ylmethyl)-pentanoic acid ethyl ester (50 mg, 0.18 mmol) in DMF (5 ml) were added (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (75 mg, 0.22 mmol) and K2CO3 (75 mg, 0.54 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 60° C. for 3 hours. The solution was cooled and poured into water (100 ml) and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc twice. The combined organics were dried (MgSO4), filtered and concentrated. The remaining residue was purified via silica gel flash column chromatography (Companion, 4 g silica gel, 20-100% EtOAc/hexanes) to give 85 mg (108%) of the title compound.
Reaction SMILES: [Na].Br[C:3]1[N:10]=[C:9]([NH2:11])[CH:8]=[C:7]([NH2:12])[C:4]=1[C:5]#[N:6].[CH3:13][OH:14]>>[NH2:12][C:7]1[C:4]([C:5]#[N:6])=[C:3]([O:14][CH3:13])[N:10]=[C:9]([NH2:11])[CH:8]=1
Reactant: CO
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [Na]
Product: COc1nc(N)cc(N)c1C#N
Temperature: 150 °C
Yield: 70 %

Procedure:
A heavy walled, sealable tube suitable for microwave heating was charged with 3 mL of methanol and 40 mg (1.7 mmol) of sodium. The mixture was stirred until all of the sodium had reacted, then 212 mg (1.00 mmol) of 2-bromo-4,6-diaminonicotinonitrile was added. The tube was sealed, and the mixture was heated with a microwave apparatus at 150° C. for 10 minutes then cooled and concentrated under reduced pressure. The residue was suspended in 10 mL of water, and extracted with ethyl acetate (1×20 mL, then 2×10 mL). The combined ethyl acetate layers were back extracted with brine (1×10 mL), dried over MgSO4, filtered, and concentrated to a solid. This was purified via silica gel chromatography, eluting with 60:40 hexanes:ethyl acetate to provide 114 mg (70%) of a white solid.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[CH2:8]([NH:15][CH2:3][CH:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: C=C(C)C(=O)OC
Solvent: CO
Product: COC(=O)C(C)CNCc1ccccc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 78.9 %

Procedure:
A mixture of methyl methacrylate (7 mL, 0.067 mol, 1.0 equiv), benzylamine (6 mL, 0.055 mol, 0.8 equiv) in methanol (5 mL) was stirred at 70° C. for 2 days. After evaporation of the volatiles, the crude product was purified by flash chromatography (DCM:MeOH=20:1) to give compound methyl 3-(benzylamino)-2-methylpropanoate 9 g, yield: 65%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 7.32-7.24 (m, 5H), 3.79 (s, 2H), 3.68 (s, 3H), 2.88-2.85 (m, 1H), 2.71-2.63 (m, 2H), 1.16 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:25]=[CH:26][CH:27]=1)[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=O)=[CH:17][CH:18]=2)[C:13]([CH3:23])=[C:12]1[CH3:24])[CH3:5].[CH:29]([O:32][C:33]1[CH:34]=[C:35]([C@@H:39]([NH2:41])[CH3:40])[CH:36]=[CH:37][CH:38]=1)([CH3:31])[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:29]([O:32][C:33]1[CH:34]=[C:35]([C@@H:39]([NH:41][C:20]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:11]([CH2:10][C:9]2[CH:8]=[C:7]([CH:27]=[CH:26][CH:25]=2)[O:6][C@@H:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:28])[C:12]([CH3:24])=[C:13]3[CH3:23])=[O:22])[CH3:40])[CH:36]=[CH:37][CH:38]=1)([CH3:31])[CH3:30]
Reactant: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: CC(C)Oc1cccc([C@H](C)N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(OC(C)C)c4)ccc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (50 mg, 0.13 mmol, 1 equiv) in DCM (2 mL) was added (S)-1-(3-isopropoxyphenyl)ethanamine (34 mg, 0.16 mmol, 1.2 equiv), DIEA (70 μL, 0.39 mmol, 3 equiv) and HATU (50 mg, 0.13 mmol, 1 equiv). The reaction mixture was stirred 2 h at room temperature. The solvent was removed in vacuo. The residue was dissolved in AcOEt and washed with a 0.5N HCl aqueous solution, a saturated NaHCO3 solution and brine, dried over MgSO4. The filtrate was concentrated to obtain the crude product which was purified by flash chromatography (AcOEt/Hexane 0->50%) to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].[O-2].[Mg+2]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:15][C:14]2[CH:13]=[C:12]([CH3:11])[CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: Cc1cccc(Nc2ccc([N+](=O)[O-])cc2)c1
Temperature: 200 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To a mixture of 4-nitro-fluorobenzene (250 mg, 1.77mmol) and 3-methyl aniline (190 mg, 1.77mmol) in 4 mL of water in a sealed tube was added magnesium oxide (86 mg, 2.126 mmol). The suspension was stirred at 200° C. for 2 days. The reaction was cooled to ambient temperature and the suspension was diluted with water and filtered to remove insoluble material. The aqueous layer was extracted 3 times with ethyl acetate (50 mL) and the combined organic layers were washed with boronic acid (5%, 50 mL) and water, dried over magnesium sulfate and concentrated in vacuo to provide (4-Nitro-phenyl)-m-tolyl-amine (190 mg, 47% yield). ). RP18-HPLC RT: 7.020 minutes; API MS: 229.20 (M+1).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[S:7][CH:8]=1)([CH3:3])[CH3:2].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][OH:32])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>C(#N)C>[OH:32][CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:19]1[CH2:18][CH2:17][C:15]2([O:14][CH2:13][CH2:12][N:11]([C:9]([C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)=[O:10])[CH2:16]2)[CH2:21][CH2:20]1
Reactant: OCCc1cccc(CBr)c1
Reactant: CC(C)c1csc(C(=O)N2CCOC3(CCNCC3)C2)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1csc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)n1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of (4-isopropylthiazol-2-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 66, step b) (0.28 g) and 2-(3-(bromomethyl)phenyl)ethanol (example 6, step a) (0.171 g) in acetonitrile (20 mL) was treated with triethylamine (0.276 mL) and the reaction mixture stirred for 2 hours at 20° C. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using 2.5% methanol in dichloromethane with 1% triethylamine as solvent to afford the subtitled compound. Yield 0.25 g.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]1[O:22][C:21]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=2[O:14]1.[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1>>[O:22]1[C:21]2[CH:20]=[CH:19][C:17]([NH:18][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([N:25]4[C:24]([CH3:23])=[CH:28][C:27]([CH3:29])=[N:26]4)[N:11]=3)=[CH:16][C:15]=2[O:14][CH2:13]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Reactant: Nc1ccc2c(c1)OCO2
Product: Cc1cc(C)n(-c2nc(Nc3ccc4c(c3)OCO4)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, 3,4-(methylenedioxy)aniline and 3,5-dimethylpyrazole. LC-ESI-HRMS of [M+H]+ shows 360.148 Da. Calc. 360.14605 Da, dev. 5.4 ppm.