Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6](=[O:17])[CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:33](OCC)(=[O:39])[C:34](OCC)=[O:35]>CN(C=O)C>[CH2:10]([N:7]1[CH2:8][CH2:9][N:4]2[C:1](=[O:3])[CH:2]=[C:33]([OH:39])[C:34]([OH:35])=[C:5]2[C:6]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)N1CCN(Cc2ccccc2)C(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 4-acetyl-1-benzylpiperazin-2-one (0.49 g, 2.1 mmol) in DMF (10 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (2.5 mL, 2.5 mmol) was added and stirred at the temperature for 30 min. The resultant solution was treated with diethyl oxalate (0.43 mL, 3.1 mmol), and stirred at room temperature overnight. The resultant mixture was then treated with additional lithium bis(trimethylsilyl)amide in THF (10 mL, 10 mmol) and stirred at room temperature for 6 h. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1.C=O.[BH3-][C:42]#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:42])[CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: O=C1CC(c2cc(Br)ccc2OC2CCNCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(F)c2)N1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(F)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (150 mg, 0.25 mmol) in methanol (10 mL) was added an aqueous solution (37 wt %, Aldrich) of formaldehyde (0.03 mL, 0.38 mmol) and NaCNBH3 (25 mg, 0.38 mmol). The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (MeOH:EtOAc:triethylamine=12:88:5) to give racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-methyl-4-piperidinyloxy)-phenyl]-6-chloro-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 100 mg, 65%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:22])[CH:3]=1.[OH:23][C@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>>[OH:23][C@H:24]1[CH2:28][CH2:27][N:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH2:13][C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:22])[CH:3]=2)[CH2:25]1
Reactant: Cc1cc(Cl)c2ccc(OCc3ccc(C#N)cc3)cc2n1
Reactant: O[C@H]1CCNC1
Product: Cc1cc(N2CC[C@H](O)C2)c2ccc(OCc3ccc(C#N)cc3)cc2n1
Yield: 87.7 %

Procedure:
A solution of 1.42 g of (4.6 mmol) of 4-(4-chloro-2-methyl-quinolin-7-yloxymethyl)-benzonitrile and 1.11 g (12.5 mmol) of (S)-3-hydroxypyrrolidine in 1-methyl-2-pyrrolidine (25 ml) was heated under nitrogen at 100° C. (oil bath temperature) for 23 h. The reaction mixture was concentrated in a high vacuum, the residue taken up in methylene chloride, which was washed with water, saturated NaCl solution and then dried over magnesium sulphate. The solvent was removed in vacuo, the residue triturated with MeOH, filtered off by suction, washed subsequently with MeOH and ether and then dried in a high vaccum to give 1.45 g (83.86%) of the (S)-4-[4-(3-hydroxy-pyrrolidin-1-yl)-2-methyl-quinolin-7-yloxymethyl]-benzonitrile as a brown solid. ISP mass spectrum, m/e: 360.2 (M+1 calculated for C22H21N3O2: 360.2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C1([O:23][C:24]([O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=O)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:24]([O:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:23])[CH2:15][CH2:16]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(OCCC2CCNCC2)cc1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Product: CCOC(=O)COC(=O)N1CCC(CCOc2ccc(Br)cc2)CC1
Yield: 54.6 %

Procedure:
The procedure described in Example 4.3. is repeated. Starting from 1.76 g (6.19 mmol) of 4-{2-[(4 bromophenyl)oxy]ethyl} prepared in Step 9.2., and 1.39 g (6.19 mmol) of ethyl {[(phenyloxy)carbonyl]oxy}-acetate, prepared in accordance with Example 1.1., gives 1.4 g of product in oil form.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)c(I)c1
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(Sc2cc(F)ccc2Br)cc1

Procedure:
Prepared from 4-methyl-benzenethiol and 1-bromo-4-fluoro-2-iodo-benzene.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:12]([NH:14][CH3:15])=[O:13].[C:26](Cl)(=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>C(Cl)(Cl)Cl>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][CH2:20][N:19]1[C:18]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N:8]=[C:43]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CNC(=O)c1ccc(NCCCN(C)C)c(N)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cc(C(=O)NC)ccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
Triethylamine (0.77 ml) was added to a solution containing 3-amino-4-{[3-(dimethylamino)propyl]amino}-N-methylbenzamide (1.44 g) in chloroform (10 ml), and then a solution containing stearoyl chloride (1.51 g) in chloroform (5 ml) was added thereto while being cooled with ice. After being stirred for 1.5 hours at room temperature, the reaction mixture was diluted with chlorofonr, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.00 ml) was added to a solution containing the residue (2.78 g) in ethanol (25 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 4N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.77 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1-10:1), thereby yielding the entitled compound (2.11 g) as grayish yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18](NC(C)C)([CH3:20])[CH3:19].C([Li])CCC.C1(=O)CCC1>>[O:15]=[C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[S:10][C:11]=2[C:17]2([CH2:20][CH2:18][CH2:19]2)[O:16]1
Reactant: COC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: CC(C)NC(C)C
Agent: O=C1CCC1
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)Nc1nc2c(s1)C1(CCC1)OC2=O

Procedure:
Methyl 2-(tert-butoxycarbonylamino)thiazole-4-carboxylate (purchased from Combi-Blocks), diisopropylamine, butyllithium, and cyclobutanone (purchased from Aldrich) were processed using the procedure as described for Example 3D to obtain the title compound. MS (ESI+) m/z 297 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:31])[CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=3)[CH2:20]2)=[O:13])=[C:5]([N+:32]([O-])=O)[CH:4]=1.C(Cl)Cl>C(O)C>[NH2:32][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=1[CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:31])[CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=2)[CH2:20]1)=[O:13]
Reactant: COc1ccc2c(c1)CC(N(C)CCCNC(=O)Cc1cc(OC)c(OC)cc1[N+](=O)[O-])CC2
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2c(c1)CC(N(C)CCCNC(=O)Cc1cc(OC)c(OC)cc1N)CC2

Procedure:
The title compound here is prepared from 1-[2-(4,5-dimethoxy-2-nitro-phenyl)-1-oxo-ethylamino]-3-[N-methyl-N-(7-methoxy-1,2,3,4-tetrahydro-naphth-2-yl)-amino]-propane (8.2 g, 0.0174 mol) analogously to Example S(c). Yield: 7.4 g. Rf value: 0.2 (alumina, eluant: 98 parts by volume of methylene chloride+2 parts by volume of ethanol).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH2:11]([NH2:13])[CH3:12]>>[CH2:11]([NH:13][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1)[CH3:12]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CCNc1ccc([N+](=O)[O-])nc1
Yield: 97 %

Procedure:
Using analogous procedures to those described in the portion of Note [9] immediately above that is concerned with the preparation of starting materials, 5-bromo-2-nitropyridine was reacted with ethylamine to give 5-ethylamino-2-nitropyridine in 97% yield; 1H NMR: (DMSOd6) 1.96 (t, 3H), 3.21 (m, 2H), 7.05 (m, 1H), 7.4 (br s, 1H), 7.87 (m, 1H), 8.12 (m, 1H); Mass Spectrum: M+H+ 168; which in turn was converted into 5-(N-tert-butoxycarbonyl-N-ethylamino)-2-nitropyridine in 81% yield; 1H NMR: (CDCl3) 1.27 (t, 3H), 1.5 (s, 9H), 3.82 (m, 2H), 7.94 (m, 1H), 8.24 (m, 1H), 8.54 (m, 1H); Mass Spectrum: M+H+ 268; which in turn was converted into 2-amino-5-(N-tert-butoxycarbonyl-N-ethylamino)pyridine in 59% yield; 1H NMR: (CDCl3) 1.12 (t, 3H), 1.4 (br s, 9H), 3.58 (q, 2H), 6.48 (d, 1H), 7.24 (m, 1H), 7.89 (m, 1H); Mass Spectrum: M+H+ 238; and which in turn was converted into N-[5-(N-tert-butoxycarbonyl-N-ethylamino)pyridin-2-yl]-2-[4-(6,7-dimethoxyquinazolin-4-yloxy) phenyl]acetamide; Mass Spectrum: M+H+ 560.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([O:16][C@H:17]1[CH2:51][N:20]3[C:21](=[O:50])[C@@H:22]([NH:41][C:42]([C:44]4[CH:48]=[C:47]([CH3:49])[O:46][N:45]=4)=[O:43])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][C@@H:30]4[CH2:35][C@@:31]4([C:36]([O:38]CC)=[O:37])[NH:32][C:33](=[O:34])[C@@H:19]3[CH2:18]1)=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1.CO.O.O.[OH-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]([O:16][C@H:17]1[CH2:51][N:20]3[C:21](=[O:50])[C@@H:22]([NH:41][C:42]([C:44]4[CH:48]=[C:47]([CH3:49])[O:46][N:45]=4)=[O:43])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][C@@H:30]4[CH2:35][C@@:31]4([C:36]([OH:38])=[O:37])[NH:32][C:33](=[O:34])[C@@H:19]3[CH2:18]1)=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](Oc3nc4cc(F)ccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: Cc1cc(C(=O)N[C@H]2CCCCC/C=C\[C@@H]3C[C@@]3(C(=O)O)NC(=O)[C@@H]3C[C@@H](Oc4nc5cc(F)ccc5c5ccccc45)CN3C2=O)no1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)N[C@H]2CCCCCC=C[C@@H]3C[C@@]3(C(=O)O)NC(=O)[C@@H]3C[C@@H](Oc4nc5cc(F)ccc5c5ccccc45)CN3C2=O)no1
Temperature: 40 °C

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-ethyl 2-(3-fluorophenanthridin-6-yloxy)-6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (846 mg, 1.21 mmol) was dissolved in tetrahydrofuran (6 mL), methanol (3 mL), and water (3 mL) and lithium hydroxide monohydrate (76 mg, 1.8 mmol) was added. The reaction mixture was heated at 40° C. for 4 h. The mixture was cooled to rt and partitioned between 2 N HCl and dichloromethane. The organic layer was concentrated under reduced pressure and then azeoptroped with toluene and chloroform to provide the title compound (0.812 g, quantitative yield) as a colorless solid that was used without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:33]1([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)#[CH:32]>CC#N.O>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][C:33]3([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:27])[CH3:29]
Reactant: C#CC1(O)CCCCC1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Solvent: CC#N
Solvent: O
Product: Cc1cc2ccc(C#CC3(O)CCCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclohexyl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (83) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 1-ethynylcyclohexanol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.75 (d, J=8 Hz, 1H), 7.68 (s, 1H), 7.58 (m, 3H), 7.40 (d, J=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H), 7.28 (s, 1H), 5.17 (s, 1H), 2.60 (s, 3H), 1.91 (m, 2H), 1.57-1.71 (m, 8H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 3.5 min run): tR (min)=2.66.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[CH:23][C:21]=1[NH2:22].C(O)(C)C>CC(O)CCC>[F:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[CH:23][C:21]=1[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: COCCOc1cc2nncc(Cl)c2cc1OC
Reactant: Cc1cc(F)c(N)cc1O
Solvent: CC(C)O
Solvent: CCCC(C)O
Product: COCCOc1cc2nncc(Nc3cc(O)c(C)cc3F)c2cc1OC

Procedure:
A suspension of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.2 g, 0.74 mmol), (prepared as described for the starting material in Example 2), and 2-fluoro-5-hydroxy-4-methylaniline (126 mg 0.89 mmol) in 2-pentanol (2.5 ml) was heated at reflux for 7.5 hours. After cooling, isopropanol was added and the solid was filtered off, washed with isopropanol and ether, and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline as the hydrochloride salt (yellow solid 196 mg, 64%).
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:14][CH:15]([F:19])[C:16](F)=[O:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:14][CH:15]([F:19])[C:16](=[O:17])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C=CN1CCCCC1
Reactant: O=C(F)C(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
Ethyl 3-piperidin-1-ylacrylate (94%, 9.4 g, 48 mmol) was initially charged in toluene (100 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (5.0 g, 51 mmol) was introduced. Triethylamine (7.7 g, 77 mmol) was then added to the reaction mixture. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 h, warmed to room temperature. The reaction mixture was washed with deionized water (50 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. This gave ethyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 12.3 g; purity according to GC: 85.4%; yield: 83.4%).
Reaction SMILES: [CH2:1]([N:8](CC)[C:9]1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][C:10]=1[CH2:11][N:12]([CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1)[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][N:14]=1)[C:2]1C=CC=CC=1>C(O)C.[C].[Pd]>[F:38][C:35]([F:36])([F:37])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:32]=1)[CH2:28][N:12]([CH2:11][C:10]1[CH:43]=[C:44]([C:47]([F:50])([F:49])[F:48])[CH:45]=[CH:46][C:9]=1[NH:8][CH2:1][CH3:2])[C:13]1[N:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][N:18]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N(CC)Cc2ccccc2)nc1
Agent: [Pd]
Solvent: CCO
Product: CCNc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
Ethyl 4-{2-[[2-(benzyl-ethyl-amino)-5-trifluoromethyl-benzyl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (4.07 g) is dissolved in ethanol (60 ml), and thereto is added 10% palladium-carbon (500 mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 30 minutes. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-ethylamino-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (3.1 g). MS (m/z): 653 [M+H]+
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[O:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[O:20]1[CH:24]=[CH:23][C:22]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)=[CH:21]1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Reactant: OB(O)c1ccoc1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2ccoc2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 2 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and furan-3-boronic acid. The title compound (45 mg) was obtained as a pale solid, m/z 347 (MH+).
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[CH2:4][C:3](=[O:11])[O:2]1.[H-].C([Al+]CC(C)C)C(C)C.Cl.CCOCC>ClCCl>[CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[CH2:4][CH:3]([OH:11])[O:2]1
Reactant: O=C1CC2CCCCC2CO1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CCOCC
Product: OC1CC2CCCCC2CO1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2.0 g (13 mmol) of (4a alpha, 8a alpha)(rac)-octahydro-3H-2-benzopyran-3-one in 65 mL of dry dichloromethane was added dropwise, over 30 min, 14 mL (14.3 mmol) of a 1.0M solution of diisobutylaluminum hydride in dichloromethane. After further stirring at -78° C. for 45 min the mixture was warmed to 0° C. over 2 hours, stirred at 0° C. for 10 min, and then 1.0M aqueous HCl was added dropwise until a pH 0-1 was reached. After addition of 60 mL of ether, phase separation and extraction of the aqueous portion with 3×50 mL of ether, the combined organic solutions were washed with 5% KHCO3, dried (MgSO4) and concentrated under vacuum to 1.60 g (80%) of racemic (4a alpha, 8a alpha)-octahydro-1H-2-benzopyran-3-ol. TLC Rf 0.41 (SiO2, ether, molybdophosphoric acid-blue).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18](=[S:20])[NH2:19].[Cl:21][CH2:22][C:23]([CH2:25]Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH:8]=[C:7]2[C:18]1[S:20][CH:25]=[C:23]([CH2:22][Cl:21])[N:19]=1
Reactant: NC(=S)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Reactant: O=C(CCl)CCl
Solvent: Cc1ccccc1
Product: ClCc1csc(-c2cn(CC3CCOCC3)c3c(Cl)cccc23)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
A mixture of 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carbothioic acid amide (920 mg, 3.0 mmol), 1,3-dichloroacetone (571 mg, 4.50 mmol) in toluene (30 ml) was stirred at 40° C. for 18 h. The reaction mixture was concentrated in vacuo, and the obtained crystals were washed with 10% dichloromethane (v/v) in n-heptane to give 7-chloro-3-[4-(chloromethyl)-[1,3]-thiazol-2-yl]-1-(tetrahydropyran-4-yl)methyl-1H-indole (590 mg, 1.5 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31](O)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][C:10]=1[CH3:34].[CH3:35][NH:36][CH2:37][C@@H:38]([C@H:40]([C@@H:42]([C@@H:44]([CH2:46][OH:47])[OH:45])[OH:43])[OH:41])[OH:39].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:35][N:36]([CH2:37][C@H:38]([OH:39])[C@@H:40]([OH:41])[C@H:42]([OH:43])[C@H:44]([OH:45])[CH2:46][OH:47])[C:31]([C:28]1[N:20]2[C:19]([CH2:18][N:17]([C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[C:10]([CH3:34])[CH:11]=3)=[O:16])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1)=[O:32]
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)cc1C
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)n3Cc3ccccc32)cc1C
Reaction time: 8 h

Procedure:
To a solution of 10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 14, Step E (0.70 g, 1.55 mmol), N-methyl-D-glucamine (0.36 g, 1.84 mmol) and 1-hydroxybenzotriazole monohydrate (0.23 g, 1.72 mmol) in N,N-dimethylformamide (6 mL) wad added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.33 g, 1.72 mmol) followed by N,N-diisopropylethyl amine (0.41 mL, 2.30 mmol). The reaction mixture was stirred overnight, then was diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow foam. Purification by flash chromatography on silica gel using a solvent system of 10% methanol in chloroform provided the title compound, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a pale, yellow foam (0.63 g).