Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[C:7](OC)=[CH:6][S:5][CH:4]=1.[CH3:10][C@@H:11]([OH:15])[C@@H:12]([OH:14])[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:10][CH:11]1[O:15][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:14][CH:12]1[CH3:13]
Reactant: C[C@H](O)[C@@H](C)O
Reactant: COc1cscc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1Oc2cscc2OC1C
Yield: 21.5 %

Procedure:
A solution of 3,4-dimethoxythiophene (7.2 g, 50 mmol), meso-2,3-butanediol (5.4 g, 60 mmol), and p-toluenesulphonic acid (0.2 g) in toluene (100 ml) was heated at 100° C. under a continuous argon flow for 24 h. The reaction mixture was then poured into methylene chloride (200 mL) and the organic phase washed with a 1M aqueous solution of sodium hydrogen carbonate and brine, dried with anhydrous magnesium sulphate and concentrated. This resulted in a mixture of cis and trans product that could be separated by column chromatography, yielding pure cis (2.8 g, 16%) and trans (1.83 g, 11%) 2,3-dimethyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[N:3]=1.[NH2:21][C:22]1[CH:26]=[C:25]([C:27]#[N:28])[NH:24][N:23]=1.CO>CN(C=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:26]=[C:25]([C:27]#[N:28])[NH:24][N:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccccc2n1
Reactant: N#Cc1cc(N)n[nH]1
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
A mixture of (4-chloroquinazoline-2-yl)(4-fluorophenyl)methanone from Example 3 (580 mg, 2.02 mmol), and 3-amino-1H-pyrazole-5-carbonitrile (218 mg, 2.02 mmol) in DMF (5 mL) was stirred at rt overnight. MeOH (10 mL) was then added to this mixture, and the precipitate was filtered washed with MeOH, and dried to afford 3-(2-(4-fluorobenzoyl)quinazolin-4-ylamino)-1H-pyrazole-5-carbonitrile (170 mg, 23.4%) 1H NMR (300 MHz, DMSO-d6) δ 6.89 (s, 1H), 7.40 (d, 2H), 7.83 (s, 1H), 7.98 (m, 2H), 8.11 (m, 2H), 8.56 (s, 1H), 11.18 (s, 1H), 13.84 (s, 1H); LC-MS (ESI) m/z 359 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH3:20])([CH3:19])[C@@H:10]([OH:18])[C@H:11]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:21][CH:22]=1)[O:8][C:9]([CH3:20])([CH3:19])[C@@H:10]([OH:18])[C@@H:11]2[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)[C@@H](N1CCCCC1)[C@H](O)C(C)(C)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1ccc2c(c1)[C@@H](N1CCCCC1)[C@H](O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
6-Acetyl-3,4-dihydro-2,2-dimethyl-trans-4-piperidino-2H-benzo[b]pyran-3-ol (1.00 g) was dissolved in methanol (10 ml) and water (2 ml) and treated with sodium borohydride (0.10 g) with stirring at room temperature during 5 minutes. After an additional 2 hours stirring, the reaction mixture was diluted with water (100 ml). Extraction using diethyl ether gave 1-hydroxy-1-[trans-2,2-dimethyl-3-hydroxy-4-piperidinochroman-6-yl]-ethane (1.00 g) which was dissolved in dry ether and treated with ethereal hydrogen chloride giving the hydrochloride salt (0.90 g) m.p. 179°-181° C. as a white powder from ethanol-ether.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCOCC1>[CH2:30]([O:37][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCc4ccccc4)c3)nc12

Procedure:
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and benzyl alcohol in dioxane. ES-MS m/e (%): 499 (M+Na+, 40), 477 (M+H+, 100).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1>>[NH2:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:38]3[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cccnc1
Product: NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (R)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 105.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6) tR=0.8 min, m/z=458.0 [M+H]+.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH:23]2[O:27][CH:26]([CH2:28]Br)[CH2:25][O:24]2)[CH2:6]1)(=O)C.[N-:30]=[N+:31]=[N-:32].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[N:30]([CH2:28][CH:26]1[CH2:25][O:24][CH:23]([C@@H:7]2[CH2:6][C@H:5]([SH:4])[CH2:9][N:8]2[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[O:27]1)=[N+:31]=[N-:32]
Reactant: CC(=O)S[C@H]1C[C@@H](C2OCC(CBr)O2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCC1COC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)O1
Yield: 70.9 %

Procedure:
A solution of (2S,4S)-4-acetylthio-2-(4-bromomethyl-1,3-dioxolan-2-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.67 g) and sodium azide (0.24 g) in N,N-dimethylformamide (25 ml) was stirred at 60° C. for 1.5 hours, and the mixture was poured into a mixture of water (250 ml) and ethyl acetate (200 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in a mixture of methanol (8 ml) and tetrahydrofuran (8 ml), and then deacetylated by reacting the resultant product with 28% solution of sodium methoxide in methanol (0.7 ml) to give (2S,4S)-2-(4-azidomethyl-1,3-dioxolan-2-yl)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.99 g) in substantially the same manner as that of Preparation 7-1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[C:12]([O:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22])(=[O:16])[C:13]([CH3:15])=[CH2:14]>CC(C)=O>[OH:11][C:4]1[CH:3]=[C:2]([NH:1][C:21]([NH:20][CH2:19][CH2:18][O:17][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[O:22])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: Nc1ccc(C(=O)O)c(O)c1
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCCNC(=O)Nc1ccc(C(=O)O)c(O)c1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
15.3 g (0.1 mol) 4-amino-2-hydroxy-benzoic acid was dissolved in 100 ml acetone. 17.06 g (0.11 mol) 2-isocyanatoethyl methacrylate was dissolved in 15 ml acetone and added dropwise to the 4-amino-2-hydroxy-benzoic acid solution. The temperature rose to 32° C. during the addition. The reaction was allowed to continue for two hours at room temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in a mixture 200 ml acetone and 50 ml methanol. The solution was added to 1 l water while stirring. 2-hydroxy-4-{3-[2-(2-methyl-acryloyloxy)-ethyl]-ureido}-benzoic acid precipitated from the medium and was isolated by filtration. 2-hydroxy-4-{3-[2-(2-methyl-acryloyloxy)-ethyl]-ureido}-benzoic acid was washed twice with 150 ml water and dried. 28.5 g (92.5%) of 2-hydroxy-4-{3-[2-(2-methyl-acryloyloxy)-ethyl]-ureido}-benzoic acid was isolated (melting point: 208-210° C.)
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:5][C:4]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:28][CH3:29])[CH2:3]1.[OH-].[Na+].CC(O)=O>C(O)C.O>[O:34]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:5][C:4]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:28][CH3:29])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(OC)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(OC)c(OCC(=O)O)cc2S(=O)(=O)C1
Temperature: 40 °C
Yield: 97.2 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 47; 1.2 g) was dissolved in ethanol (20 ml). Sodium hydroxide (0.5) dissolved in H2O (1 ml) was added and the reaction mixture was warmed to 40° C. for 30 min. AcOH (1 ml) was added and the solvent was removed at reduced pressure. The residue was partitioned between DCM/H2O and the organic layer was separated and dried. Trituration of the residue with n-hexane gave the title compound 1.1 g (97%) as a solid. NMR (400 MHz; CDCl3): 0.75-0.85 (m, 3H), 0.9 (t, 3H), 1.0-1.7 (m, 8H), 3.2 (q, 2H), 3.65 (s, 3H), 3.65-3.85 (m, 2H), 4.7 (s, 2H), 6.4 (s, 1H), 7.0 (t, 1H), 7.1 (d, 2H), 7.3 (t, 2H), 7.5 (s, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][NH:18][C:17](=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](Br)[CH:26]=1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:18]2[CH2:19][CH:15]([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)[CH2:16][C:17]2=[O:20])[CH:26]=1)[CH3:22]
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC1CCCC1
Reactant: CCOC(=O)c1cccc(Br)c1
Product: CCOC(=O)c1cccc(N2CC(c3ccc(OC)c(OC4CCCC4)c3)CC2=O)c1
Yield: 66.5 %

Procedure:
A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-pyrrolidin-2-one (300 mg, 1.1 mmol) and 3-bromobenzoic acid ethyl ester (303 mg, 1.32 mmol) was treated according to General Procedure I to provide 310 mg of the desired product as a white solid. Yield: 67%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[CH:9]=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[C:12]=1C)([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][C:30](=[O:49])[CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=2)[C:36]=1[CH2:37]C)([CH3:28])([CH3:27])[CH3:26].COC(=O)CC1C(C)=NN(C([N+]([O-])=O)C2C=CC=CC=2)C=1C>>[C:1]([O:5][C:6](=[O:24])[CH2:7][C:8]1[C:9]([CH3:25])=[N:10][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH:12]=1)([CH3:2])([CH3:3])[CH3:4].[C:25]([O:29][C:30](=[O:49])[CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([NH2:46])=[CH:44][CH:45]=2)[C:36]=1[CH3:37])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCc1c(CC(=O)OC(C)(C)C)cnn1Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1c(CC(=O)OC(C)(C)C)cnn1Cc1ccc([N+](=O)[O-])cc1
Agent: COC(=O)Cc1c(C)nn(C(c2ccccc2)[N+](=O)[O-])c1C
Product: Cc1c(CC(=O)OC(C)(C)C)cnn1Cc1ccc(N)cc1
Product: Cc1nn(Cc2ccc(N)cc2)cc1CC(=O)OC(C)(C)C

Procedure:
The following examples can be prepared in analogous fashion to example 1.1, employing in the reduction step [5-methyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid tert-butyl ester or in the case of example 2.59 [5-ethyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid tert-butyl ester (preparation according to WO2008/138876) instead of [3,5-dimethyl-1-(nitrobenzyl)-1H-pyrazol-4-yl-acetic acid methyl ester and employing in the amide coupling the corresponding carboxylic acids as coupling partners. Each example except for example 2.59 is a single regioisomer; the required intermediates [1-(4-amino-benzyl)-3-methyl-1H-pyrazol-4-yl]-acetic acid tert-butyl ester and [1-(4-amino-benzyl)-5-methyl-1H-pyrazol-4-yl]-acetic acid tert-butyl ester are obtained in a single reaction and are separable by MPLC.
Reaction SMILES: [BH4-].[Na+].C(O)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH3:28])[C:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=3)=[N:16][S:15](=[O:27])(=[O:26])[NH:14]2)=[CH:9][N:8]=1>C(OCC)(=O)C>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@:13]2([CH3:28])[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=3)[NH:16][S:15](=[O:26])(=[O:27])[NH:14]2)=[CH:9][N:8]=1
Reactant: CC1(c2ccc(Cl)nc2)NS(=O)(=O)N=C1c1ccc(Cl)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@]1(c2ccc(Cl)nc2)NS(=O)(=O)N[C@H]1c1ccc(Cl)c(F)c1
Reaction time: 2 h
Yield: 60.7 %

Procedure:
Sodium borohydride (1.00 g, 26.4 mmol) was gradually added to an ethanol (63 ml) solution of the compound (7.13 g, 19.1 mmol) obtained in Step 7 above under ice cooling and the resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and then the residue obtained was diluted with ethyl acetate, washed with 1 N aqueous hydrochloric acid solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=1:2 (v/v)] to give the title compound (4.36 g, 59%) as a pale yellow solid.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][C:21]([NH:5][CH2:4][CH2:3][Br:2])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCBr)OCc1ccccc1
Reaction time: 19 h

Procedure:
To a solution of 2-bromoethylamine hydrochloride (25 g: a product of Tokyo Kasei Kogyo Co., Ltd.) and triethylamine (34 ml) in methylene chloride (450 ml), benzyloxycarbonyl chloride (19 ml) was added dropwise over a period of 20 minutes and the mixture was agitated at room temeprature for 19 hours. The resulting reaction mixture was washed with water, with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride succeedingly, whereupon the separated organic layer was dried and, then, removed off the solvent by distilling it of under reduced pressure. The residue was cooled with ice and the crystals were collected by filtration and washed with hexane, whereby the above-identified compound was obtained (29.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9]C=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:15]([NH2:17])[CH3:16].C(Cl)CCl.CC[N:24](C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[NH2:1][C:2]1[C:3]([C:4]([NH:17][CH2:15][CH3:16])=[O:6])=[CH:7][N:24]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCN
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)c1cncc([N+](=O)[O-])c1N
Temperature: 0 °C
Reaction time: 3 h
Yield: 47.6 %

Procedure:
To a solution of 2-amino-3-nitrobenzoic acid (CXXVI) (366 mg, 2.0 mmol) in DCM (5 mL) and DMF (1 mL) was added ethylamine hydrochloride and EDC. The mixture was cooled to 0° C. under argon before added DIPEA. The reaction was stirred at room temperature for 3 h. The solution was concentrated under vacuum, dissolved in water and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated under vacuum. The residue was purified on a silica gel column (100% CHCl3→5:95 MeOH[7N NH3]:CHCl3) to give 4-amino-N-ethyl-5-nitronicotinamide (CXXVII) as a yellow solid (200 mg, 0.95 mmol, 47.6% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.14 (t, J=7 Hz, 3H), 3.28 (q, J=6 Hz, 2H), 8.97 (s, 1H), 9.06 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH:8]([O-])([O-])[O:9]C.[CH3:13]O>>[CH3:13][O:7][CH:6]([O:9][CH3:8])[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: COC([O-])[O-]
Reactant: O=Cc1ccsc1
Reactant: CO
Product: COC(OC)c1ccsc1

Procedure:
224 g of 3-thiophenecarbaldehyde and 265 g of methyl orthoformate are dissolved in 200 ml of methanol. One g of strongly acidic ion-exchange resin Amberlite IR-120(H+) [manufactured by Rohm & Haas] is added thereto, and the mixture is refluxed with heating for 2 hours. The resin is separated by filtration, and the filtrate is condensed under reduced pressure. The residue is distilled to give 294 g of 3-dimethoxymethylthiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])([O-:19])=[O:18].C(N(CC)CC)C.CN(C)C=O>O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:13][CH2:12][CH:11]([NH:14][S:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N+:17]([O-:19])=[O:18])(=[O:27])=[O:28])[CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: NC1CCN(c2nc3ccc(Cl)cc3s2)C1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCN(c2nc3ccc(Cl)cc3s2)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
A mixture of 1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-ylamine (2.49 g), 2-nitrobenzenesulphonyl chloride (2.40 g), triethylamine (3.02 mL) and dimethylformamide (15 mL) was stirred at 60° C. for 3 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (2.01 g). Yield: 47
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:6](=[O:23])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2.COC(=O)C.[C:30]([O:34][C:35](=[O:42])[NH:36][CH2:37][CH2:38][CH2:39][CH2:40]Br)([CH3:33])([CH3:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:6](=[O:23])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:40][CH2:39][CH2:38][CH2:37][NH:36][C:35]([O:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:42])[CH:9]=2
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: COC(=O)Cc1cc2ccc(O)cc2n(Cc2ccccc2)c1=O
Solvent: COC(C)=O
Product: COC(=O)Cc1cc2ccc(OCCCCNC(=O)OC(C)(C)C)cc2n(Cc2ccccc2)c1=O

Procedure:
The title compound is prepared using the conditions of Example 75 and (1-benzyl-7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester in place of 7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)acetic acid methyl ester and (4-bromobutyl)carbamic acid tert-butyl ester in place of (2-bromoethyl) carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[NH2:14].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[NH2:14]
Reactant: [H][H]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(Cl)cc(N)c1N

Procedure:
A slurry of 2-amino-5-chloro-3-nitro-benzoic acid methyl ester (1.8 g, 8.40 mmol) and 10% Pd/C (0.5 g) in methanol (50 mL) was hydrogenated with a hydrogen balloon for 2 h. After completion of reaction, the reaction mixture was filtered over a celite bed and concentrated to dryness. The resulting residue was purified by column chromatography using 30% ethyl acetate in hexane to obtain the title compound as off white solid.
Reaction SMILES: [C:1](Cl)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[P:17]([O:22]C)([O:20][CH3:21])[O:18][CH3:19].[P:24]([O-:29])([O:27][CH3:28])[O:25][CH3:26]>>[OH:15][C:1]([P:17]([O:18][CH3:19])(=[O:22])[O:20][CH3:21])([P:17]([O:20][CH3:21])(=[O:22])[O:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:13])([P:17]([O:20][CH3:21])(=[O:22])[O:18][CH3:19])[P:24]([O:27][CH3:28])(=[O:29])[O:25][CH3:26]
Reactant: O=C(Cl)CCCCCCCCCCC(=O)Cl
Reactant: COP([O-])OC
Reactant: COP(OC)OC
Product: COP(=O)(OC)C(O)(CCCCCCCCCCC(O)(P(=O)(OC)OC)P(=O)(OC)OC)P(=O)(OC)OC
Temperature: 90 °C
Reaction time: 10 h

Procedure:
5.34 g (0.02 mol) 1,12-dodecanedioyl dichloride was added dropwise, with stirring, in a nitrogen atmosphere, to a mixture of 4.96 g (0.04 mol) of trimethyl phosphite and 4.40 g (0.04 mol) of dimethyl phosphite at room temperature. The mixture was stirred for 10 hrs at 90° C. and the reaction mixture was evaporated under reduced pressure. The oily residue (9.8 g) showed a broad signal at δ=22.3 ppm in the 31P nmr spectrum.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:24].[Na+]>C1COCC1.C(OCC)C>[OH:24][CH2:3][CH2:2][CH2:1][N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: [OH-]
Reactant: C=CCn1ccc2cc(C=O)ccc21
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ccc2c(ccn2CCCO)c1

Procedure:
In a 10 mL round-bottom flask, 1-Allyl-1H-indole-5-carbaldehyde (169 mg, 0.91 mmol) is dissolved in 0.5 mL of anhydrous THF. To this solution is added 0.5 M of 9-BBN in THF (2 mL, 1.0 mmol). The reaction is allowed to stir at room temperature for 1 hr, whereupon a 1M solution of NaOH (2.5 mL) is added. The organic layer is diluted with 10 mL of diethyl ether and the aqueous layer is removed. The organic layer is washed 3×10 mL with 1M NaOH, followed by 2×10 mL water and 2×10 mL saturated NaCl solutions. The organic layer is then dried over Na2SO4 and the solvent is removed under reduced pressure to afford 1-(3-hydroxy-propyl)-1H-indole-5-carbaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].[N:35]1([C:41]([C:43]2[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=2)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:9]=[C:10]([C:46]4[CH:45]=[CH:44][C:43]([C:41]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[O:42])=[CH:48][CH:47]=4)[C:11]=23)=[C:19]([F:25])[CH:20]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COc1ccc(Cn2nc(-c3ccc(C(=O)N4CCOCC4)cc3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 85 °C
Yield: 11.5 %

Procedure:
A mixture of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.30 g, 0.612 mmol; prepared as in Example 7, Step B), Cs2CO3 (0.299 g, 0.918 mmol), and 4-(morpholine-4-carbonyl)phenylboronic acid (0.151 g, 0.643 mmol) in DME (3 mL) was degassed under nitrogen for 10 minutes and tetrakistriphenylphosphinepalladium (0.035 g, 0.03 mmol) was added. The reaction mixture was heated at 85° C. for 15 hours. The precipitate was removed by filtration with a mixture of EtOAc and MeOH. The filtrate was concentrated and the crude material was purified by silica gel flash column chromatography (1% MeOH in CH2Cl2) to afford 39 mg (12%) of the desired product. LRMS (APCI pos) m/e 554.1 (M+1).