Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C@@H:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[CH2:14][NH:15][C:16]([C:18]1[S:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:17].[N+](C1C=CC([O:33][C:34](=O)[NH:35][C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]3=[O:48])=[CH:38][C:37]=2[F:49])=CC=1)([O-])=O>>[F:49][C:37]1[CH:38]=[C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])[CH:40]=[CH:41][C:36]=1[NH:35][C:34]([N:12]1[CH2:13][C@@H:9]([OH:8])[C@H:10]([CH2:14][NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:11]1)=[O:33]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@@H]1CNC[C@H]1O)c1ccc(Cl)s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1O)c1ccc(Cl)s1

Procedure:
79.7 Using general method H, to (3S,4S)-5-chloro-thiophene-2-carboxylic acid (4-hydroxy-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (3R,4S)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Colorless solid. MS 491.0 ([M+H]+)
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C@@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:34][NH:35][O:36][CH3:37].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.O>[CH3:37][O:36][N:35]([CH3:34])[C:18]([C@H:15]1[CH2:14][CH2:13][C@@H:12]([C:10](=[O:11])[C:9]2[CH:8]=[CH:7][C:6]([Cl:5])=[CH:22][CH:21]=2)[CH2:17][CH2:16]1)=[O:20]
Reactant: CNOC
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)c2ccc(Cl)cc2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)[C@H]1CC[C@@H](C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (2.87 g, 15.0 mmol) was added portionwise to a stirred solution of cis-4-(4-chlorobenzoyl)-cyclohexanecarboxylic acid (2.0 g, 7.5 mmol), DMAP (5 mg), HOBt (5 mg) and N,O-dimethylhydroxylamine hydrochloride (1.46 g, 15 mmol) in dichloromethane (40 mL). Triethylamine (2.28 g, 3.14 mL, 22.5 mmol) was added dropwise, and the reaction mixture was stirred at room temperature overnight. The resulting solution was poured into water, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give cis-4-(4-chlorobenzoyl)-cyclohexanecarboxylic acid, methoxy-methyl amide as a colorless oil (1.6 g. 69%); 1H NMR (CDCl3, 300 MHz) δ 7.82 (d, J=8.5 Hz, 2H,), 7.41 (d, J=8.5 Hz, 2H), 3.69 (s, 3H), 3.35 (quin, J=5 Hz, 1H), 3.16 (s, 3H), 2.80 (sept, J=4 Hz, 1H), 2.15 (m, 2H), 1.89 (m, 2H), 1.72 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[O-:11][CH2:12][CH3:13].[Na+]>C(O)C.O1CCCC1>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][O:11][CH2:12][CH3:13]
Reactant: CC[O-]
Reactant: Fc1ccc(CBr)c(Br)c1
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOCc1ccc(F)cc1Br

Procedure:
By the method of Example 1, Step A, 10.9 g (0.041 mole) of 2-bromo-4-fluorobenzyl bromide and 18.2 ml of a 21% by weight solution of sodium ethoxide in ethanol were reacted in 50 ml of tetrahydrofuran, yielding 7.18 g of ethyl 2-bromo-4-fluorobenzyl ether.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=2)[N:6]=[CH:5][C:4]=1[OH:15]>C(#N)C.[O-2].[O-2].[Mn+4]>[OH:15][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:3]=1[CH:2]=[O:1])=[N:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2
Reactant: COc1ccc2ncc(O)c(CO)c2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: COc1ccc2ncc(O)c(C=O)c2n1
Temperature: 35 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Manganese dioxide (530 mg, 6.05 mmol, 5.0 eq) is added at room temperature to a stirred solution of 4-hydroxymethyl-6-methoxy-[1,5]naphthyridin-3-ol (250 mg, 1.21 mmol, 1.0 eq) in acetonitrile (10 mL) and the resulting mixture is stirred at 35° C. for 1 hour. The solid is filtered off, washed with acetone (3×10 mL) and the filtrate is concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 1:4, v/v) to afford 3-hydroxy-6-methoxy-[1,5]naphthyridine-4-carbaldehyde as a light yellow solid (180 mg, 73% yield).
Reaction SMILES: [C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([N:25]=[C:26]([C:28]([O:30]C(C)C)=[O:29])[N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1>[C:34]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([N:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)OC(=O)c1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.1 %

Procedure:
1.85 g of isopropyl [6-[3-[4-(diphenylmethoxy) piperidino]propoxy][1,2,4]triazolo[1,5-b]pyridazin-2-yl]carboxylate was dissolved in 18 ml of tetrahydrofuran; 3.8 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 3.5 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was diluted with water and washed with ethyl acetate; 1 N hydrochloric acid was added to ajust pH 4.5. The mixture was crystallized by the addition of ethanol-acetone (1:2), collected by filtration, washed with water and ethyl acetate and dried to yield 1.33 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[C:16]([N:18]([CH3:31])C(=O)[C:20]=2C2C3C(=CC=CC=3)NC=2)=[O:17])=[CH:7]1.[CH3:33][OH:34]>[C].[Pd]>[CH3:32][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2([C:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[NH:6][CH:7]=3)[CH2:20][C:33](=[O:34])[N:18]([CH3:31])[C:16]2=[O:17])=[CH:7]1
Reactant: CN(C)CCCn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)N(C)C2=O)c2ccccc21
Reactant: CO
Agent: [Pd]
Product: CN(C)CCCn1cc(C2(c3c[nH]c4ccccc34)CC(=O)N(C)C2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.5 %

Procedure:
To a solution of 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-N-methylmaleimide (60 mg, 0.14 mmol) in MeOH (3 mL) was added a small amount of 10% palladium-carbon, and the whole was stirred at room temperature for 1 day under hydrogen atmosphere. The palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (dichloromethan:methanol=8:1) to obtain 3-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-1-methyl-2,5-dioxopyrrolidine (49 mg, 81.5%) as pale red solids.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]1[CH:30]=[C:29]([C:31]2[S:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[O:28][N:27]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:9]([CH2:25][C:26]2[CH:30]=[C:29]([C:31]3[S:32][C:33]([Cl:36])=[CH:34][CH:35]=3)[O:28][N:27]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(-c2ccc(Cl)cc2)[nH]1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2cc(-c3ccc(Cl)s3)on2)c(-c2ccc(Cl)cc2)n1
Reaction time: 0.25 h

Procedure:
500 mg (2.0 mmol) of 2-(4-Chlorophenyl)-3H-imidazole-4-carboxylic acid ethyl ester was dissolved in 5 ml of DMF and 2.6 g (8 mmol) of cesium carbonate were added at RT. After stirring for 15 min, 445 mg (1.6 mmol) of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added. The reaction was stirred at room temperature for 16 h. The reaction solution was filtered and the product was purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid. Yield: 480 mg; MS (LCMS-ES+): m/e=448.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])([O-:3])=[O:2].[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23][OH:24])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1ccnc1
Reactant: C=O
Solvent: Cc1ccccc1C
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1ccnc1CO

Procedure:
In the manner given in Example 1, 5-nitro-2-(imidazol-1-yl)benzophenone is heated in a bomb with paraformaldehyde in xylene to 140° C. to give 5-nitro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][O:21]2)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(CCO)ccc1OCc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(CCOC2CCCCO2)ccc1OCc1ccccc1
Yield: 90.7 %

Procedure:
A mixture of Example 69B (0.89 g, 3.27 mmol), 3,4-dihydro-2H-pyran (1.49 mL, 16.34 mmol) and p-TsOH.H2O (5 mg) in dichloromethane (20 mL) were stirred at room temperature overnight. The reaction solution was dried with silica gel powder (15 g). 20% ethyl acetate in hexanes (1 L) was used to run flash chromatography to give the title compound (1.06 g, 91%). MS (DCI) m/z 375.13 (M+NH4)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.42–1.62 (m, 4 H) 1.68 (m, 1 H) 1.79 (m, 1 H) 2.88 (t, J=6.60 Hz, 2 H) 3.45 (m, 1 H) 3.59 (m, 1 H) 3.70 (m, 1 H) 3.94 (m, 1 H) 4.58 (t, J=3.38 Hz, 1 H) 5.21 (s, 2 H) 7.03 (d, J=8.59 Hz, 1 H) 7.28–7.48 (m, 6 H) 7.77 (d, J=2.15 Hz, 1 H).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1O[CH2:11]1.C=CCCCCCCC=C>>[O:3]1[CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:1]1
Reactant: C(CCCC1CO1)CCC1CO1
Agent: C=CCCCCCCC=C
Product: C=CCCCCCCC1CO1
Yield: 54 %

Procedure:
The organic phase was first rapidly distilled in order to remove the catalyst from it, then was rectified, with 47.0 g (0.276 mol) of 1,2,9,10-diepoxydecane, with a yield of 54%; 1.96 g of unreacted 1,9-decadiene (3%); and 23.0 g of 1,2-epoxy-9-decene (29%) being obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]2[O:15][CH2:14][O:13][C:12]=12)[C:6]([O:8]C)=[O:7].[OH-].[Li+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]2[O:15][CH2:14][O:13][C:12]=12)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(OC)c2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc2c1OCO2
Reaction time: 4 h

Procedure:
Combine methyl 3-methoxy-4,5-methylenedioxybenzoate (0.84 g, 4.0 mmol) and tetrahydrofuran (25 mL). Add a 1 M aqueous solution of lithium hydroxide (8.0 mL, 8.0 mmol). Heat to reflux. After 4 hours, cool the reaction, concentrate in vacuo to remove most of the tetrahydrofuran. Extract with ethyl acetate. Cool in a ice bath and acidify the aqueous layer with a 6 M aqueous hydrochloric acid solution to give a solid. collect the solid by filtration and dry to give the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([N:9]2[N:18]=[C:17]3[C:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][O:30]C6CCCCO6)[CH:27]=5)[CH:20]=[CH:19][C:16]=43)=[CH:10]2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.CO>C(OCC)C>[CH:1]([N:4]1[C:8]([N:9]2[N:18]=[C:17]3[C:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=5)[CH:20]=[CH:19][C:16]=43)=[CH:10]2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(-c3cnn(CCOC4CCCCO4)c3)cc1OCC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(-c3cnn(CCO)c3)cc1OCC2
Yield: 95.9 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene 45 (134 mg, 0.27 mmol) was dissolved in diethyl ether (5 mL) and treated with 1M HCl in diethyl ether (1 mL) then methanol (5 mL). After 30 min the reaction mixture was concentrated to dryness and the resultant residue triturated in diethyl ether to give 176 as a pale cream solid (105 mg, 86%). 1H NMR (400 MHz, DMSO-d6): δ 8.32 (s, 1H); 8.23 (s, 1H); 8.19 (d, J=8.23 Hz, 1H); 8.03 (s, 1H); 7.96 (s, 1H); 7.39 (dd, J=8.24, 1.74 Hz, 1H); 7.29 (d, J=1.68 Hz, 1H); 5.46-5.36 (m, 1H); 4.34 (t, 2H); 4.17 (t, J=5.61 Hz, 2H); 3.78 (t, J=5.58 Hz, 2H); 3.13 (t, J=4.91 Hz, 2H); 1.52 (d, J=6.57 Hz, 6H). 1 Exchangeable proton not observed. LCMS: RT=10.68 min, M+H+=406
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:29]([CH:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:39]2=[O:52])=[CH:30][C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[CH:37]=1>>[OH:16][CH2:5][C:38]1([C:29]2[C:28]([OH:27])=[CH:37][C:32]3[N:33]=[C:34]([CH3:36])[S:35][C:31]=3[CH:30]=2)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:39]1=[O:52]
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2cc3sc(C)nc3cc2O)c2ccccc21
Product: CCCCCN1C(=O)C(CO)(c2cc3sc(C)nc3cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 367.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.COCCO[AlH2-]OCCOC.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(Cl)cc1
Yield: 100.5 %

Procedure:
The 2-(4-chlorophenyl)-2-methyl-propionic acid (6.10 g, 30.7 mmol) was dissolved in 120 mL of dry THF at room temperature. A 70% w/w solution of Red-Al (28.25 mL, 0.101 mol) was added dropwise via syringe over 5 minutes (vigorous bubbling). The mixture was heated to reflux for three hours. The solution was cooled to 0 C and carefully quenched with the addition of saturated sodium tartrate solution (100 mL, violent hydrogen evolution) and 100 mL of water. The aqueous mixture was extracted with ethyl acetate, and the combined organic was washed with diluted NaHCO3 solution, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford 2-(4-chlorophenyl)-2-methyl-propan-1-ol as a colorless oil (5.70 g, 99%). The material was used without purification. 1H NMR (CDCl3, 400 MHz) δ 7.32 (s, 5H), 3.62 (d, J=4.4 Hz, 2H), 1.33 (s, 6H), 1.23 (t, J=4.4 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[CH:7][CH:6]=1)=O.[NH2:33][C:34]1[C:39]([CH:40]([OH:42])[CH3:41])=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH2:13][C@@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]2[N:33]=[C:34]3[C:39]([CH:40]([OH:42])[CH3:41])=[CH:38][CH:37]=[CH:36][N:35]3[CH:2]=2)=[CH:10][CH:9]=1
Reactant: CC(O)c1cccnc1N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(=O)CBr)cc1)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CN4C(=O)c5ccccc5C4=O)NC(=O)OC(C)(C)C)cc3)nc12
Yield: 87.4 %

Procedure:
A mixture of 1,1-dimethylethyl {(1S)-2-{4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (1.90 g, 3.79 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4.72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), and concentrated to give the title compound (1.79 g, 87%) as a light pink solid. MS (ES+) m/e 541 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:26](=[O:30])[N:27]([CH3:29])[CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CC(C)=O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:26](=[O:30])[N:27]([CH3:28])[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCC4)c3n2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Temperature: 45 °C
Reaction time: 12 h
Yield: 80.7 %

Procedure:
To a suspension of methyl 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate (2.0 g, 4.9 mmol) in THF (6 mL) was added 1M LiOH (aq) (6 mL, 1.2 equiv) and the slurry stirred at 45° C. for 12 hours (the slurry became clear). After cooling to room temperature, the THF was evaporated and the reaction mixture was treated with 1 N HCl until pH=1-2. The resulting precipitate was filtered and the filtrate extracted with 20% Isopropanol/CH2Cl2 (3×100 mL), the combined organic layers dried, filtered, and concentrated to a tan solid. The tan solid was triturated in acetone giving the desired product as a tan solid (1.56 g, 73% yield) which was used without further purification. MS: (M+H)=395.5
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].C(=O)([O-])[O-].[K+].[K+].[I:36][C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[OH:47].O>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])[C:14]2[S:18][N:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:47][C:38]1[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:45])[F:46])=[CH:42][C:37]=1[I:36])#[N:2]
Reactant: Oc1ccc(C(F)(F)F)cc1I
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3I)c(C#N)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68, 25 g, 57.5 mmol) in DMSO (125 mL) was added potassium carbonate (20.4 g, 148 mmol) followed by dropwise addition of the 2-iodo-4-(trifluoromethyl)phenol (Preparation 224, 17.4 g, 60.6 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was poured into water (1 L) and extracted with ethyl acetate (3×300 mL). The organic layers were combined and washed with water (2×250 mL), dried over sodium sulfate and concentrated in vacuo. The residue was slurried in methanol (150 mL) for 1 hour before filtering and drying under vacuum to afford 33.92 g of the title compound as a white solid (83%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10]([CH2:17][OH:18])=[CH:11][S:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:28][O:29][CH2:30]Cl>ClCCl>[CH2:1]([S:8][C:9]1[C:10]([CH2:17][O:18][CH2:28][O:29][CH3:30])=[CH:11][S:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1scc(CO)c1SCc1ccccc1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCc1csc([N+](=O)[O-])c1SCc1ccccc1

Procedure:
[4-(benzylthio)-5-nitrothien-3-yl]methanol (3.9g, 13.9 mmol) in dichloromethane (8 mL) was reacted with diisopropylethylamine (7.42 mL, 3 equivalents) and methoxymethyl chloride (2.38 mL, 2.25 equivalents) at 25° C. 16 hours. The reaction was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel using a Biotage-40m column eluting with dichloromethane to give 3-(benzylthio)-4-[(methoxymethoxy)methyl]-2-nitrothiophene as a yellowish oil, (4.32 g, 94%). 1H NMR (300 MHz, CDCl3) δ ppm 3.36 (s, 3H), 4.20 (s, 2H), 4.34 (s, 2H), 4.62 (s, 2H), 7.13 (m, 3H), 7.21 (m,2H), 7.40 (s, 1H)
Reaction SMILES: C1C=CN=CC=1.F.[CH3:8][O:9][C:10](=[O:52])[CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][C@H:17]1[C@H:21]([Cl:22])[CH2:20][C@@H:19]([O:23][Si](C(C)(C)C)(C)C)[C@@H:18]1[C:31]1[CH:36]=[CH:35][C:34]([CH:37]([O:44][Si](C(C)(C)C)(C)C)[CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:33][CH:32]=1>CC#N>[CH3:8][O:9][C:10](=[O:52])[CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][C@H:17]1[C@H:21]([Cl:22])[CH2:20][C@@H:19]([OH:23])[C@@H:18]1[C:31]1[CH:32]=[CH:33][C:34]([CH:37]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[OH:44])=[CH:35][CH:36]=1
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](c2ccc(C(O[Si](C)(C)C(C)(C)C)C3CCCCC3)cc2)[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cl
Agent: F
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)CCC/C=C\C[C@@H]1[C@@H](c2ccc(C(O)C3CCCCC3)cc2)[C@H](O)C[C@H]1Cl
Reaction time: 1 h
Yield: 232.6 %

Procedure:
HF-pyridine (0.60 mL) was added to a 0° C. CH3CN solution of chloride 6-2 (24 mg, 20%) and the mono TBS derivative (36 mg, 36%). The reaction was stirred for 1 h, and then was quenched by addition of saturated NaHCO3 solution. The mixture was extracted with dichloromethane (3×30 mL) and the combined dichloromethane solution dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (20% ethyl acetate/hexanes) gave the title diol 6-3 (37 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:15](Br)([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Yield: 77 %

Procedure:
20 g of 4-bromo-4'-hydroxybiphenyl, 12 g of isopropyl bromide, 45 g of potassium carbonate and 200 ml of N,N'-dimethylformamide are reacted in an analogous manner to Example 1(a) to give 18 g of 4-bromo-4'-(isopropoxy)biphenyl.