Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl[C:20]([F:26])([F:25])C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:25][CH:20]([F:26])[O:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COC(=O)C(F)(F)Cl
Reactant: COC1CN(C(=O)c2ccc([N+](=O)[O-])c(O)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1CN(C(=O)c2ccc([N+](=O)[O-])c(OC(F)F)c2)C1
Temperature: 120 °C
Yield: 69.5 %

Procedure:
(3-Hydroxy-4-nitrophenyl)(3-methoxyazetidin-1-yl)methanone (Preparation 115, 300 mg, 1.19 mmol) and methyl 2-chloro-2,2-difluoroacetate (258 mg, 1.78 mmol) were dissolved in dry DMF (2 mL). Potassium carbonate (328 mg, 2.38 mmol) was added and the reaction was heated to 120° C. under microwave irradiation for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic solution was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 20% hexanes in ethyl acetate to 100% ethyl acetate to afford the title compound as a yellow oil (250 mg, 67.3%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=[O:16].[OH-].[Na+]>S(=O)(=O)(O)O>[Br:5][C:6]1[CH:15]=[CH:14][C:13]([N+:1]([O-:4])=[O:2])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=[O:16]
Reactant: O=C1CCCc2c(Br)cccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCCc2c(Br)ccc([N+](=O)[O-])c21
Reaction time: 0.75 h
Yield: 336.6 %

Procedure:
To prepare this compound, 90% fuming nitric acid (0.115 gram, 0.165 mmol) was added to a solution of 5-bromo-3,4-dihydro-2H-naphthalen-1-one (0.34 g, 1.50 mmol) in 3 mL concentrated sulfuric acid at 0° C. After 45 minutes, the mixture was poured into ice, and 6 N aqueous sodium hydroxide (9 mL) was added very slowly. That mixture was extracted twice with EtOAc (40 mL each), and the two extracts were combined. The combined EtOAc extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was subjected to flash chromatography (40% EtOAc/hexanes) and recrystallization (EtOAc/hexanes) to afford 0.15 g (38%) of 5-bromo-3,4-dihydro-8-nitro-2H-naphthalen-1-one. 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J=8.2, 1H), 7.25 (d, J=8.2, 1H), 3.07 (t, J=6.2, 2H), 2.74 (t, J=6.7, 2H), 2.18-2.25 (m, 2H).
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:31]=1[CH:30]([NH:32][C:33]1[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH2:43])[CH:39]=3)[N:34]=1)[CH2:29][CH2:28]2>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:31]=1[CH:30]([NH:32][C:33]1[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH:43][C:1]([NH:20][CH:17]4[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]4)=[O:2])[CH:39]=3)[N:34]=1)[CH2:29][CH2:28]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCC(N)CC1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(C)CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-methyl-piperidin-4-ylamine and rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172); MS: m/e=446.7 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:14]#[N:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[C:28]([N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1)(N1C=CN=C1)=[O:29].NCCN1C[CH2:47][O:46][CH2:45][CH2:44]1>C1COCC1.ClCCl>[C:14]([C:13]1[CH:16]=[CH:17][C:18]([O:19][C:20]2[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)=[C:11]([S:8]([N:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:28]([NH:35][CH2:39][CH2:38][N:37]3[CH2:36][CH2:47][O:46][CH2:45][CH2:44]3)=[O:29])[CH2:7][CH2:6]2)(=[O:10])=[O:9])[CH:12]=1)#[N:15].[CH:18]([O:19][CH:20]([CH3:25])[CH3:21])([CH3:17])[CH3:11]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(N)CC2)c1
Reactant: NCCN1CCOCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(NC(=O)NCCN3CCOCC3)CC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(1-(5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl)-piperidin-4-yl)-3-(2-morpholinoethyl)urea (22) is prepared according to the following method as an alternative to the method of Example 32. 3-(4-aminopiperidin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)-benzonitrile (1.002 g), prepared according to Example 1, and carbonyldiimidazole (420 mg, 1.1 eq.) were combined in THF (15 mL) and stirred at room temperature. After 5 hours, starting material was consumed (confirmed by HPLC). 4-(2-aminoethyl)morpholine (512 mg, 2.0 eq.) was added and the mixture was stirred 19 hours. Concentration in vacuo provided a white solid, which was resuspended in dichlormethane, partitioned with water, and the aqueous layer extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield a white solid. Trituration with isopropyl ether yielded a 96% pure product according to HPLC. The powder was suspended in minimal amounts of hot methanol, stirred at 60° C. for 30 minutes, cooled in an ice bath and vacuum filtered to obtain the product as a white powder (831 mg, 60.7% yield, 98% purity).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28]([OH:30])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH:42]1[CH2:43][CH2:44][CH2:45][CH2:46]1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:30])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CCCC1
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1CCCC1
Yield: 61.6 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (100 mg, 0.25 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopentyl-amine (8e) (72 mg, 0.29 mmol) in dimethylformamide (2.5 mL) were added N,N-diisopropylethylamine (0.1 mL, 0.74 mmol) and HATU (141 mg, 0.37 mmol). Stirring was continued at room temperature for 20 h, whereafter water (25 mL) was added and the mixture extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopentyl-amide (288) (97 mg, 62.28%) as a light yellow sticky solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49](Cl)(=[O:51])=[O:50]>C(#N)C>[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccc3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 74.6 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.126 g, 0.274 mmol) was dissolved in acetonitrile (6.0 mL), and the solution was treated with triethylamine (0.0760 mL, 0.548 mmol) and 2-chlorobenzenesulfonyl chloride (0.0867 g, 0.411 mmol) to obtain 4-(2-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.130 g, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH2:25]([O:28][CH3:29])[C:26]#[CH:27].CCN(CC)CC>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:27]#[C:26][CH2:25][O:28][CH3:29])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C#CCOC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: COCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C

Procedure:
A solution of the title compound of Example 5 (540.3 mg), methyl propargyl ether (0.14 mL), PdCl2 (PPh3)2 (21.1 mg), and 0.75 mL Et3N in 3 mL DMF is heated at 90° C. for 1 hr. The reaction mixture is cooled to room temperature and partitioned between EtOAc and H2 0. The aqueous layer is washed with EtOAc (4×). The combined organic layers are dried over Na2SO4 and condensed to obtain a dark residue. The residue is diluted with MeOH, adsorbed onto silica, and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized from EtOAc/hexanes to yield 0.218 g of the desired product as a white solid.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@H:24]([C:26](OC)=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Li+]>O1CCCC1>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@H:24]([CH2:26][OH:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COC(=O)[C@@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@@H](CO)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.9 %

Procedure:
To a solution of methyl (2S,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 13, 350 mg, 0.580 mmol) in Tetrahydrofuran (THF) (7 ml) at 0° C. lithium borohydride (0.568 ml, 1.160 mmol) was added and the reaction mixture was stirred at room temperature and under nitrogen atmosphere for 3 days. Volatiles were evaporated in vacuo and the residue was dissolved in Methanol (2 ml)/HCl 1 N in water (3 ml). After 1 h stirring combined solvents were evaporated in vacuo. The residue was dissolved in Ethyl acetate (4 ml) and washed with NaHCO3 sat. sol. (2×3 ml). Organic phase was dried and evaporated and the residue was purified by flash chromatography on silica gel using a Biotage SNAP 10 g as column and Dichloromethane/Methanol 98:2 as eluent affording the title compound (110 mg, 0.191 mmol, y=33.0%).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:17])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].[C:20]1([OH:26])C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.O>[C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:20]=[O:26])[C:7]=1[OH:17])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCC(C)(C)c1ccc(O)c(C(C)(C)CC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(C)(C)c1cc(C=O)c(O)c(C(C)(C)CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4-di-t-amylphenol (70 g, 0.30 mole) was dissolved in 200 ml absolute ethanol in a 1 L round bottom flask equipped with a water-cooled condenser. Sodium hydroxide (82 g, 2.0 moles) was dissolved in 80 ml water and added while still hot to the solution of phenol. Chloroform (149 g, 1.25 mole) was added in 2 ml portions over a 45-minute period. The resulting yellow-brown mixture was stirred 2 hours while cooling to ambient temperature. The mixture was extracted into 400 ml of hexanes and the organic layer rinsed with 400 ml of 1M HCl. The organic layer was isolated in a separatory funnel and dried over anhydrous magnesium sulfate. The mixture was filtered and rotoevaporated to a thick syrup, and the IR spectrum of the crude product showed the characteristic aldehyde carbonyl stretching frequency. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[S:9][C:4]=2[NH:5][C:6](=[S:8])[N:7]=1.CCN(CC)CC.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C.CCOC(C)=O>[CH3:12][C:11]1[C:3]2[C:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])=[N:7][C:6](=[S:8])[NH:5][C:4]=2[S:9][C:10]=1[CH3:13]
Reactant: CCOC(=O)Cl
Reactant: Cc1sc2[nH]c(=S)nc(N)c2c1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc(=S)[nH]c2sc(C)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a suspension of 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-thione (211 mg, 1 mmol) in DMF (5 mL) was added Et3N (0.21 mL, 1.5 mmol) and ethyl chloroformate (0.143 mL, 1.5 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and evaporated. The residue was purified on Biotage SP-1 eluting with EtOAc/hexane to give the title compound (154 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ 1.22 (t, J=7.2 Hz, 3H), 2.38 (s, 3H), 2.39 (s, 3H), 4.25 (q, J=7.2 Hz, 2H), 7.25-7.21 (m, 2H). MS 284 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[N:6][CH:7]=1.[Li]CCCC.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=1)[CH:28]=[O:29]>C1COCC1.CCCCCC>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:28]([C:2]2[CH:7]=[N:6][C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[CH:4][CH:3]=2)[OH:29])[CH:30]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: Fc1ccc(Nc2ccc(Br)cn2)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(Br)cc1C(O)c1ccc(Nc2ccc(F)cc2F)nc1
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
(5-Bromo-pyridin-2-yl)-(2,4-difluoro-phenyl)-amine (100 mg; 0.35 mmol) in THF (2.2 ml) is treated at −78 C with nBuLi (0.48 ml of a 1.5M solution in hexane; 0.77 mmol). After 10 min at −78 C, 5-bromo-2-methoxybenzaldehyde (75 mg; 0.35 mmol) in THF (0.3 ml) is added and stirring continued for 30 min. at −78 C. The reaction mixture is poured on water/ice and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated to dryness. Purification via chromatography (SiO2; TBME/hexanes 3/7) yields the title compound (60 mg; 40%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].COC1C=CC(C[NH2:30])=CC=1>CN(C=O)C.C(O)(C(F)(F)F)=O>[NH2:30][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: COc1ccc(CN)cc1
Reactant: O=C(OCc1ccccc1)c1c(Cl)c2ccccc2[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Nc1c(C(=O)OCc2ccccc2)c(=O)[nH]c2ccccc12
Temperature: 115 °C
Reaction time: 0.25 h
Yield: 116.5 %

Procedure:
Benzyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 66b) (0.55 g, 1.75 mmol) was dissolved in DMF (8 mL) and 4-methoxybenzylamine (0.56 mL, 4.31 mmol) was added. The reaction was heated at 115° C. for 30 minutes, then cooled to room temperature and poured into ice water. The resultant precipitate was dissolved in 10 mL TFA and stirred at room temperature for 15 minutes, then the mixture was poured into ice water. The resultant precipitate was collected, dissolved in dichloromethane, dried over MgSO4, filtered and evaporated to give the crude benzyl 4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylate (600 mg) which was used as this without further purification. MS 295 (MH+).
Reaction SMILES: [CH3:1][NH:2][NH2:3].Cl[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH2:23][CH:22]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])[O:21][N:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7]>O1CCCC1>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[CH:22]1[O:21][N:20]=[C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][N:2]([CH3:1])[NH2:3])[CH2:13][CH2:12]3)[S:15][CH:16]=2)[CH2:23]1
Reactant: O=C(CCl)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CC1
Reactant: CNN
Solvent: C1CCOC1
Product: CN(N)CC(=O)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl hydrazine (532 μL, 10.0 mmol) in tetrahydrofuran (1 mL) at 0° C. was added dropwise a solution of 2-chloro-1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]ethanone (i.e. the product of Example 2, Step A) (425 mg, 1.0 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature overnight, and then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as an oil (0.59 g weight including residual tetrahydrofuran), which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: Brc1cncnc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1ccc(-c2cncnc2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 81.7 %

Procedure:
5-Bromopyrimidine (954 mg, 6 mmol) and 1.0 g (5.0 mmol) of 4-bromophenylboronic acid were dissolved in 20 ml of N,N-dimethylformamide and 5 ml of water. Tetrakistriphenylphosphine palladium (590 mg, 0.5 mmol) and 830 mg (7.5 mmol) of sodium carbonate were added to the solution, and the mixture was stirred at 80° C. for 2.5 hr. Ethyl acetate (60 ml) and 8.5 ml of water were added to the reaction solution. The mixture was filtered through Celite. The filtrate as an organic layer was washed five times with 30 ml of water. The organic layer was dried over anhydrous sodium sulfate and was filtered. The solvent was then removed by distillation, and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give 960 mg (yield 82%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].O>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:8]=[CH:7][C:3]=1[C:4]([N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])=[O:5]
Reactant: CCNCC
Reactant: CC(C)C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(NC(=O)C(C)C)cc1Cl
Reaction time: 8 h

Procedure:
The crude 2-chloro-4-(2'-methylpropionamido)benzoyl chloride from the preceding reaction in dry THF (10 ml) was added dropwise with stirring over 10-15 minutes to a solution of diethylamine (1.46 g) in dry THF (10 ml), at 0°-5° C. After stirring at 0°-10° C. the reaction mixture was stood overnight at room temperature, poured into cold water and extracted with ethyl acetate. This extract was dried and evaporated to give a viscous gum which crystallised slowly and was then recrystallised from ethyl acetate to give 2-chloro-4-(2'-methylpropionamido)-N,N-diethylbenzamide as white crystals (0.507 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:25]([CH2:36][CH:37]=[O:38])[CH2:24]1)(=[O:22])=[O:21])=[CH:5]2.[CH2:39](O)[CH2:40][OH:41].CC1C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])[C:6]([S:20]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH:25]([CH2:36][CH:37]3[O:41][CH2:40][CH2:39][O:38]3)[CH2:24]1)(=[O:21])=[O:22])=[CH:5]2
Reactant: OCCO
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CC1CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CC1CC1OCCO1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
In toluene (10 mL) were dissolved 4-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-1-(tert-butoxycarbonyl)-2-(formylmethyl)piperazine (440 mg) and ethylene glycol (71 mg, followed by the addition of p-TsOH.H2O (15 mg). The resulting mixture was heated to 60° C. and stirred for 16 hours. Ethyl acetate was added to the reaction mixture. The resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous MgSO4 and distilled under reduced pressure to remove the solvent, whereby the title compound (460 mg) was obtained as colorless amorphous.