Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl[CH2:45][C:46]1[O:47][CH:48]=[CH:49][CH:50]=1>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:29]([CH2:45][C:46]4[O:47][CH:48]=[CH:49][CH:50]=4)[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: ClCc1ccco1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4Cc4ccco4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 35.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and 2-(chloromethyl)furan (T. Reichstein et al., Ber., 63 749-754 (1930)) to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([NH2:17])=[C:11]3[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.CN(C)C=O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([N:32]=[C:33]=[O:34])[CH:25]=1>ClCCl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([NH:32][C:33]([NH:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH:9]=[CH:10][C:11]=23)=[O:34])[CH:25]=1
Reactant: COc1ccc(Br)cc1N=C=O
Reactant: Nc1ccnc2c1ccn2Cc1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1NC(=O)Nc1ccnc2c1ccn2Cc1ccncc1

Procedure:
To a solution of Compound 1d (50 mg, 0.2 mmol) in dichloromethane:dimethylformamide (4.0 mL, 3:1) is added 4-bromo-2-isocyanato-1-methoxy-benzene (50 mg, 0.2 mmol, 1 equiv.) and the reaction mixture is heated for 16 hrs, the solvent is then removed and the residue is purified using flash chromatography to afford Compound 1e as a white solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([S:21]([CH3:22])=[O:38])[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cccc2c(-c3ccnc(SC)n3)c(-c3ccc(F)cc3)nn12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCNc1cccc2c(-c3ccnc(S(C)=O)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.6 %

Procedure:
To a cold (0° C.) solution of N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-7-amine (1.51 g, 3.7 mmol) in 50 mL chloroform was added m-chloroperbenzoic acid (0.87 g, 70–75%, 3.7 mmol). The reaction was allowed to warm to rt. After stirring for 5 h, another 0.2 g m-chloroperbenzoic acid was added and the reaction was stirred for 15 min. The reaction was diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated. The crude product was recrystallized from ethyl acetate-hexanes to afford N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-7-amine (0.95 g, 60%) as an orange solid. 1H NMR (CDCl3): δ 8.40 (broad, 1H), 7.99 (d, 1H), 7.58 (m, 2H), 7.45 (t, 1H), 7.20 (t, 2H), 6.94 (d, 1H), 6.13 (d, 1H), 6.10 (broad, 1H), 3.38 (m, 2H), 2.98 (s, 3H), 1.79–1.42 (m, 4H), 0.97 (t, 3H); MS m/z 422 (M−1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:6](O)[N:5]2[N:14]=[CH:15][N:16]=[C:4]2[N:3]=1.O=P(Cl)(Cl)[Cl:19]>>[CH3:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:6]([Cl:19])[N:5]2[N:14]=[CH:15][N:16]=[C:4]2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2ncnn2c(O)c1C1CCCC1
Product: Cc1nc2ncnn2c(Cl)c1C1CCCC1

Procedure:
A mixture of 5-methyl-6-cyclopentyl-7-hydroxy[1,2,4]triazolo[1,5-a]pyrimidine (17 g, Ex. 2) and POCl3 (50 ml) was heated under reflux for 8 hours. During this operation, some of the POCl3 was distilled off. The residue was poured into a mixture of dichloromethane and water. The organic phase was separated off and dried. Removal of the solvent gave 11 g of the title compound of m.p. 87° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[NH:30]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[C@H:29]([CH3:28])[CH2:33][O:32][C:31]4=[O:34])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 30.7 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (839 mg) described in Preparation Example 61 and (R)-4-methyloxazolidin-2-one (288 mg) described in Preparation Example 25, the title compound (269 mg) was obtained.
Reaction SMILES: [CH2:1]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24](Cl)=[O:25])[CH:19]=1.C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([N:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][C:11]([F:12])([F:13])[F:14])=[O:25])[CH:19]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: FC(F)(F)CNCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N(CCc1ccccc1)CC(F)(F)F
Reaction time: 2 h

Procedure:
0.80 g (3.94 mmol) phenethyl-(2,2,2-trifluoroethyl)-amine and 3.9 mL (3.9 mmol) of a 1M sodium hydroxide solution were added dropwise to 0.77 g (4.33 mmol) 6-chloropyrimidine-4-carboxylic acid chloride in 20 mL dichloromethane while cooling with a bath of ice and ethanol. The mixture was first stirred for 2 h with cooling and then for 1 h at RT. 50 mL of a saturated sodium hydrogen carbonate solution were added and the mixture was stirred for 10 min. The organic phase was separated off, washed with water and 1M hydrochloric acid, dried on sodium sulphate, filtered and concentrated by rotary evaporation i.vac.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[N:12]=[C:11]([NH2:14])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[N:15]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]2[C:13]3[N:12]=[C:11]([NH:14][S:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)(=[O:24])=[O:23])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[N:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1nc2c(s1)-c1nc(N)ncc1CC2
Solvent: c1ccncc1
Product: Cc1nc2c(s1)-c1nc(NS(=O)(=O)c3ccccc3)ncc1CC2
Yield: 35.3 %

Procedure:
Under anhydrous conditions pyridine (5 mL) was added to 2-methyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-8-ylamine (148 mg, 0.68 mmol). The mixture was stirred at 60° C. for 1 h before benzenesulfonyl chloride (121 μL, 168 mg, 0.95 mmol) was added. After 16 h the mixture was cooled and evaporated to dryness. Flash column chromatography (20% EtOAc:hexane) gave the title product as a tan solid (86 mg, 35%): mp 265° C. (dec). Anal. RP-HPLC: tR 15.5 min (0-60% MeCN, purity 100%). 1H-NMR (DMSO-d6): δ 8.25 (s, 1H, Py-H), 8.03-7.98 (m, 2H, Ph-H), 7.62-7.55 (m, 3H, Ph-H), 2.92 (m, 4H, CH2—CH2), 2.73 (s, 3H, CH3). 13C-NMR (DMSO-d6): δ 170.15, 160.04, 156.92, 155.66, 153.95, 140.76, 132.51, 128.60, 127.70, 126.97, 118.96, 24.35, 22.94, 19.51. MS (ESI+): m/z 380.97 (M+Na)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][CH:29]([C:32]5[NH:36][C:35]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=6)=[N:34][N:33]=5)[CH2:28][CH2:27]4)=[CH:21][CH:20]=3)=[N:9][C:10]3[C:15]([CH:16]=2)=[C:14]([NH:17][NH2:18])[N:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:43](OOC)(OOC)OOC.C1(C)C(S(O)(=O)=O)=CC=CC=1>CO.C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:8]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][N:26]4[CH2:27][CH2:28][CH:29]([C:32]5[NH:36][C:35]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=6)=[N:34][N:33]=5)[CH2:30][CH2:31]4)=[CH:23][CH:24]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:43]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: COOC(OOC)OOC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: c1ccc(-c2cc3c(ccn4cnnc34)nc2-c2ccc(CN3CCC(c4nnc(-c5ccccn5)[nH]4)CC3)cc2)cc1

Procedure:
To a solution of 8-9 (4.5 g, 8.1 mmol) in 20 mL methanol and 60 mL toluene was added trimethoxy orthoformate (3.5 g, 32.5 mmol) and toluenesulfonic acid (0.1 g, 0.8 mmol). The mixture was refluxed for 10 hrs. Upon removal of the solvent, the residue was purified by flash column chromatography (100% CHCl3 to 50% CHCl3 and 50% methanol) to afford the desired product 8-10.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.[I:21]I>O1CCCC1.O>[F:13][C:14]1[CH:19]=[C:18]([I:21])[C:17]([F:20])=[CH:16][N:15]=1
Reactant: Fc1ccc(F)nc1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: Fc1cc(I)c(F)cn1
Reaction time: 1 h
Yield: 44.4 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 18.6 mL, 46.5 mmol) was added to a solution of diisopropylamine (6.51 mL, 46.1 mmol) in anhydrous tetrahydrofuran (85 mL) at −78° C. and stirred at this temperature for 1 hour. A solution of 2,5-difluoropyridine (5.0 g, 43 mmol) in anhydrous THF (12 mL) was added dropwise via cannula and the reaction was stirred at −78° C. for 3 hours. After this time, iodine (12.1 g, 47.8 mmol) in tetrahydrofuran (50 mL) was added dropwise via cannula to the reaction at −78° C. and stirred at this temperature for 1 hour after complete addition. Water (100 mL) was added to the reaction and the temperature was allowed to come to RT. The reaction was extracted with diethyl ether (3×100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated. The crude was purified via flash chromatography using an Analogix SF40-80g column and an eluant of ethyl acetate in heptane (0-10%) to afford the title compound as a yellow solid (4.60 g, 44%). LC-MS m/z 242.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.39 (t, J=3.71 Hz, 1H) 7.96 (d, J=1.56 Hz, 1H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([OH:14])=[CH:6][CH:5]=1)=[O:2].[CH3:15][N:16]=[C:17]=[O:18]>CC(C)=O.C(N(CC)CC)C>[CH3:15][NH:16][C:17](=[O:18])[O:14][C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:4]([NH:3][CH:1]=[O:2])=[CH:5][CH:6]=1
Reactant: O=CNc1ccc(O)c2c1CCCC2
Reactant: CN=C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc(NC=O)c2c1CCCC2
Yield: 87 %

Procedure:
4-Formamido-5,6,7,8-tetrahydro-1-naphthol was dissolved in anhydrous acetone and allowed to react with an excess of methyl isocyanate in a pressure bottle at room temperature for 2 days. Triethylamine was used as a catalyst. The solvent was stripped from the product under reduced pressure and the solid residue washed thoroughly with isopropyl ether. There was obtained 4-formamido-5,6,7,8-tetrahydro-1-naphthyl N-methylcarbamate, m.p. 165°-166°, in 87% yield.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:28]([CH:31]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32]1)[CH2:29][CH3:30]>CCCCCC.C1(C)C=CC=CC=1.O1CCCC1>[OH:36][C:33]1([C:15]2([O:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH2:16]2)[CH2:34][CH2:35][CH:31]([CH2:28][CH2:29][CH3:30])[CH2:32]1
Reactant: CCCC1CCC(=O)C1
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCOC1(C2(O)CCC(CCC)C2)C=CC(c2ccccc2)=CC1
Reaction time: 0.25 h

Procedure:
32 ml of 15% n-butyllithium solution in hexane are added dropwise to a suspension of 18.07 g of 4-n-octyloxy-4'-bromobiphenyl in a mixture of toluene/tetrahydrofuran at -15°. After 15 minutes, a clear solution is obtained and a mixture of 6.31 g of 3-n-propylcyclopentanone and 25 ml of toluene/tetrahydrofuran is added dropwise. After the mixture has reacted for a further 16 hours at room temperature and after conventional work-up and column chromatography, 4-(1-hydroxy-3-n-propylcyclopentyl)-4-n-octyloxybiphenyl is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[C:8](=[O:23])[CH2:7]1)=[O:5])[CH3:2].[CH:24](OCC)(OCC)OCC>>[CH2:1]([O:3][C:4]([CH:6]1[C:14]2[C:9](=[CH:10][C:11]([N:15]3[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:21]4[N:22]=[CH:24]3)=[CH:12][CH:13]=2)[C:8](=[O:23])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C1CC(=O)c2cc(Nc3ncccc3N)ccc21
Product: CCOC(=O)C1CC(=O)c2cc(-n3cnc4cccnc43)ccc21

Procedure:
A solution of (R/S)-5-(3-Amino-pyridin-2-ylamino)-3-oxo-indan-1-carboxylic acid ethyl ester (754 mg, 2.42 mmol) in triethyl orthoformate (25 mL) is heated at 145° C. for 30 min. The solvent is evaporated and the residue purified by flash chromatography eluting with Hexane/EtOAc. (R/S)-5-Imidazo[4,5-b]pyridine-3-yl-3-oxo-indan-1-carboxylic acid ethyl ester is obtained as a colourless solid. Title compound: 1H NMR: (DMSO-d6): 9.0 (s, 1H), 8.5 (d, 1H), 8.4 (d, 1H), 8.3 (s, 1H), 8.2 (d, 1H) 7.9 (d, 1H), 7.4 (dd, 1H) 4.5 (m, 1H), 4.2 (m, 2H), 3.0 (m, 2H), 1.2 (t, 3H); tR=1.2 min (System 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[Cl:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cl)cc1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A 250-mL single-neck round bottomed flask equipped with a magnetic stirrer was charged with methyl 4-chlorosalicylate (25.0 g, 134 mmol) followed by concentrated sulfuric acid (73 mL) and the resulting suspension cooled to 0° C. using an ice bath. Concentrated nitric acid (6.20 mL, 147 mmol) was then added and the reaction stirred for 1 h at 0° C. After this time, the reaction was poured into ice and the resulting precipitate collected by vacuum filtration. The filter cake was washed with water (20 mL) and then re-crystallized from hot ethanol (100 mL) to afford methyl 4-chloro-3-nitrosalicylate in 52% yield (16.0 g) as white solid: 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=2.7 Hz, 1H), 8.11 (d, J=2.7 Hz, 1H), 4.03 (s, 3H); MS (ESI) m/z 232 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[C:21]2[CH:29]=[C:28]([N:30]([CH3:32])[CH3:31])[N:27]=[CH:26][C:22]=2[N:23]=[CH:24][N:25]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:20]3[C:21]4[CH:29]=[C:28]([N:30]([CH3:32])[CH3:31])[N:27]=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:14][CH:15]=2)[C:10]([CH3:18])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1cc2c(Cl)ncnc2cn1
Reactant: Cc1nn(Cc2ccccc2)c2ccc(N)cc12
Product: Cc1nn(Cc2ccccc2)c2ccc(Nc3ncnc4cnc(N(C)C)cc34)cc12

Procedure:
Prepared according to Procedure A from 1-Benzyl-3-methyl-1H-indazol-5-ylamine and 4-chloro-6-(N,N-dimethylamino)-pyrido[3,4-d]pyrimidine; δH [2H6]DMSO 11.75 (1H,s), 8.90(1H,s), 8.62(1H,s), 8.02(1H,s), 7.70(3H,m), 7.30(5H,m), 5.62(2H,s), 3.30(6H,s) 2.50(3H,s); m/z (M+1+) 410.
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[CH:10]=[CH:9][C:3]=1[NH:4][C@@H:5]([CH3:8])[CH2:6][OH:7].C(O[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC.ClCCl>[F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[CH:10]=[CH:9][C:3]=1[N:4]([CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@@H:5]([CH3:8])[CH2:6][OH:7]
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=CN(c1ccc(F)c(F)c1F)[C@@H](C)CO)C(=O)OCC
Temperature: 25 °C
Reaction time: 22 h
Yield: 78.4 %

Procedure:
The compound (103 mg) obtained in Example 51, diethyl ethoxymethylenemalonate (108 mg) and tetrahexylammonium chloride (29 mg) were dissolved in dichloromethane (1 ml). After adding potassium carbonate (138 mg), the mixture was stirred at room temperature for 22 hours. After the completion of the reaction, the residue was filtered off and the solvent was evaporated. Then the residue thus obtained was subjected to silica gel column chromatography to thereby give 147 mg (78%) of the title compound as a colorless solid. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 63.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH:7]1[CH2:12][CH:11]2[CH2:13][CH2:14][N:8]1[CH2:9][CH2:10]2)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:3][CH2:4][CH2:6][CH:7]1[CH2:12][CH:11]2[CH2:10][CH2:9][N:8]1[CH2:14][CH2:13]2
Reactant: CCOC(=O)CC1CC2CCN1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCC1CC2CCN1CC2
Yield: 98.3 %

Procedure:
15.9 g of 2-ethoxycarbonylmethyl-quinuclidine were reduced with lithium aluminium hydride in the presence of ether under reflux to give 12.3 g of 2-hydroxyethylquinuclidine, m.p. 62°-64° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.O1CCCC1.[CH:16]([C:18]1[N:22]([CH3:23])[N:21]=[CH:20][C:19]=1[C:24]#[C:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)=[O:17].Cl>O>[OH:17][CH2:16][C:18]1[N:22]([CH3:23])[N:21]=[CH:20][C:19]=1[C:24]#[C:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cn1ncc(C#Cc2ccc(S(N)(=O)=O)cc2)c1C=O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(C#Cc2ccc(S(N)(=O)=O)cc2)c1CO
Reaction time: 1 h
Yield: 37.2 %

Procedure:
Under a nitrogen atmosphere, 1.0 M diisobutylaluminum hydride (1.70 mL, toluene solution) was added dropwise to a tetrahydrofuran (5.0 mL) solution of 4-[(5-formyl-1-methyl-1H-pyrazol-4-yl)ethynyl]benzenesulfonamide (160 mg) at −78° C., and the obtained solution was then stirred for 1 hour. Thereafter, water was added to the reaction solution, and the obtained solution was converted to an acidic solution by addition of 2 M hydrochloric acid. Then, the solution was extracted with ethyl acetate. The organic layer was washed with water, and was then dried over anhydrous sodium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, chloroform/methanol=99:1 to 95:5), so as to obtain the title compound (60 mg) in the form of a light yellow solid.
Reaction SMILES: C([Li])CCC.[CH:6]#[C:7][CH2:8][CH2:9][CH3:10].Br[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.Cl>C1COCC1.[Cl-].[Zn+2].[Cl-]>[C:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)#[C:7][CH2:8][CH2:9][CH3:10]
Reactant: C#CCCC
Reactant: Brc1cccs1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC#Cc1cccs1
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
A solution of n-butyllithium (10.0 ml, 10.0M in hexane, 0.10 mol) is added dropwise to a stirred cooled (-5° to 0° C.) solution of pent-1-yne (6.80 g, 0.10 mol) in dry THF under dry nitrogen. This mixture is stirred for 10 minutes and then a solution of dry zinc chloride (13.63 g, 0.10 mol) in dry THF is added dropwise to 2-bromothiophene (16.00 g, 0.098 mol) at a temperature of between -5° C. and 0° C. followed by addition of tetrakis (triphenylphosphine)palladium(O) (3.40 g, 2.94 mol). The mixture is stirred at room temperature overnight (glc analysis revealing a complete reaction) and poured into 10% hydrochloric acid. The product is extracted into ether (×2) and the combined ethereal extracts are washed with aqueous sodium hydrogen carbonate and dried (MgSO4). The solvent is removed in vacuo, then the product is filtered and distilled to yield 12.9 g (88%) colourless liquid.
Reaction SMILES: COC1N=CC([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][C:10]=2[CH3:22])=CC=1B1OC(C)(C)C(C)(C)O1.Br[C:33]1[CH:34]=[C:35]([Cl:40])[C:36]([Cl:39])=[N:37][CH:38]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[Cl:40][C:35]1[CH:34]=[C:33]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:11][C:10]=2[CH3:22])[CH:38]=[N:37][C:36]=1[Cl:39]
Reactant: Clc1cc(Br)cnc1Cl
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1cnc(Cl)c(Cl)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A suspension of tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (from INTERMEDIATE 31 Step B, 1.0 g, 3.14 mmol), 5-bromo-2,3-dichloropyridine (0.784 g, 3.46 mmol), potassium phosphate (1.33 g, 6.29 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.077 g, 0.094 mmol) in dioxane (12 mL) and water (1 mL) was flushed with nitrogen and stirred at 70° C. for 4 hours. After cooling down, the mixture was filtered over celite and the filter cake washed with ethyl acetate. The filtrate was diluted with ethyl acetate and water and partitioned. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated. The crude isolate was purified by silica gel chromatography (0 to 80% ethyl acetate/hexane) to give the titled compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.3 (d, J=2.1 Hz, 1H), 7.95 (s, 1H), 7.92 (d, J=7.7 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.27 (d, J=7.9 Hz, 1H), 2.35 (s, 3H), 1.65 (s, 9H).