Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].N[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.CO>C(O)(=O)C>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([S:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:16]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)[CH:21]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3nc(C)ccc23)c1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To a solution of the product from Example 10B (100 mg, 0.575 mmol) and the product from Example 9c (146 mg, 0.632 mmol) in acetic acid (1 mL) was heated at 130° C. for 1 hour. The mixture was then allowed to cool to room temperature, then methanol (5 mL) added to the solution and the resulting solid collected and washed with methanol to provide the title compound (120 mg, 56%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.29 (s, 3H), 2.66 (s, 3H), 6.73 (d, J=8.8 Hz, 2H), 6.93 (m, 1H), 7.03 (m, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.26, (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 8.53 (s, 1H), 8.77 (m, 1H), 9.76 (bs, 1H), 9.96 (bs, 1H); MS (ESI)+ m/z 375 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([O:11]C(C)(C)C)=[O:10])[CH:6]=[C:5]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[N:4]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[C:5]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[N:4]=1
Reactant: COc1cc(C(=O)OC(C)(C)C)cc(N2CCCC2=O)n1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)cc(N2CCCC2=O)n1

Procedure:
t-Butyl 2-methoxy-6-(2-oxopyrrolidin-1-yl)pyridine-4-carboxylate (D57) (0.27 g) was stirred overnight in a dioxan solution of HCl (4M; 10 mL). The solution was evaporated to dryness and dissolved in sat. aq. sodium bicarbonate. The basic aqueous solution was washed twice with ether and was then acidified to pH4 with citric acid solution (10% aq.), saturated with NaCl and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried and evaporated to a solid which was triturated with water, collected by filtration and dried at 50° C. in vacuo (silica gel desiccant). The title compound (D58) was obtained as an off-white solid (0.141 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[CH3:12][NH:13][C:14]([C:16]1[S:24][C:23]2[C:18](=[N:19][CH:20]=[CH:21][C:22]=2Cl)[CH:17]=1)=[O:15]>>[CH3:12][NH:13][C:14]([C:16]1[S:24][C:23]2[C:18](=[N:19][CH:20]=[CH:21][C:22]=2[NH:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)[CH:17]=1)=[O:15]
Reactant: CNC(=O)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: CNC(=O)c1cc2nccc(Nc3ccc4[nH]c(C)cc4c3)c2s1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-Chloro-thieno[3,2-b]pyridine-2-carboxylic acid methylamide by a procedure analogous to Example 1C. MS: 337 (MH+); HPLC Rf: 3.86 min.; HPLC purity: 98%.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:3]([C:5]2[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:27][CH2:28]1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)nn1C
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 51 %

Procedure:
As described for example 78b, 2-methyl-5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.21 mmol) was converted using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (43 mg, 51%) which was obtained as a white solid. MS: m/e=398.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1.[C:29](#[N:32])[CH:30]=[CH2:31]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][N:26]([CH2:31][CH2:30][C:29]#[N:32])[CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: Cn1nnc(-c2ccc3c(c2)c(C2=CCNCC2)cn3-c2ccc(F)cc2)n1
Solvent: ClCCl
Product: Cn1nnc(-c2ccc3c(c2)c(C2=CCN(CCC#N)CC2)cn3-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-fluorophenyl)-5-(2-methyl-5-tetrazolyl)-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (21a), (10.2 g) in dichloromethane (100 mL) was added acrylonitril (7.5 g). The mixture was stirred at room temperature for 16 hours. After evaporation of the solvent, the crude title compound 15a remained as a viscous oil which was used without further purification. Yield 12 g.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([O:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1>>[CH2:1]([N:3]([CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2]
Reactant: CN1CCC(Oc2ccc(C=O)cc2)CC1
Reactant: CCNc1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OC2CCN(C)CC2)cc1)c1ccccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 59.7 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylaminophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 4-(1-methylpiperidin-4-yloxy)benzaldehyde (94 mg) according to an analogous synthetic method to Example 264 and purified by LC-MS, the title compound (24 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(O)[C:7]3[CH:12]=[N:11][CH:10]=[N:9][C:8]=32)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:29])CC)C.C(=O)(O)[O-].[K+]>C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([F:29])[C:7]3[CH:12]=[N:11][CH:10]=[N:9][C:8]=32)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)c2ccc(Cl)cc2-c2ncncc21
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: FC1(c2ccc(Cl)cc2)c2ccc(Cl)cc2-c2ncncc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A mixture of 3.0 g of 8-chloro-5-(4-chlorophenyl)-5H-indeno[1,2-d]pyrimidin-5-ol in 50 ml of methylene chloride was cooled to 0° C. under a nitrogen atmosphere. Approximately 2.7 g of diethylaminosulfur trifluoride were added and the reaction was stirred overnight. The mixture was poured into an iced solution of potassium bicarbonate and extracted with ethyl acetate. The organic extract was washed with a sodium bicarbonate solution and a sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Crystallization from ethyl acetate/isooctane provided 2.29 g of the desired title product, m.p. 236°-237° C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([C:15]1[CH:16]=[C:17]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14].CI.Cl>C1COCC1>[C:13]([C:15]1[CH:16]=[C:17]([CH:22]([CH3:1])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14]
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C(=O)OC(C)(C)C)c1ccc(F)c(C#N)c1
Temperature: 0 °C

Procedure:
To a stirred solution of diisopropylamine in 2 ml of THF at −78° C. was added n-butyl lithium (0.61 ml). The reaction was stirred for 30 minutes after which time a solution of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (0.300 g) in THF (2 ml) was added dropwise over 20 minutes at −78° C. The reaction was warmed to 0° C. and then transferred a flask containing 2 ml THF and MeI (0.080 ml). The reaction was acidified with 2M HCl and extracted with ethyl acetate. The combined organics were then washed with brine and dried over MgSO4. The concentrated product was purified by silica gel chromatography using a solvent system of 5% to 50% ethyl acetate/hexanes to provide tert-butyl 2-(3-cyano-4-fluorophenyl)propanoate (0.140 g).
Reaction SMILES: [CH2:1]([CH:4]1[O:6][CH:5]1[C:7]([OH:9])=O)[CH2:2][CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.[OH-].[Na+]>C(OC(C)C)(=O)C>[CH:25]1([NH:28][C:7]([CH:5]2[CH:4]([CH2:1][CH2:2][CH3:3])[O:6]2)=[O:9])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: CCCC1OC1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Solvent: CN1CCOCC1
Product: CCCC1OC1C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
A flask equipped with an overhead stirrer, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with the acid of Example 1 (20.0 g, 154 mmol), and isopropyl acetate (IPAc; 200 mL) then cooled to 0±5° C. 4-Methylmorpholine (NMM, 154 mL, 17 mL) was charged to the addition funnel then added maintaining the temperature at 0±5° C. Once addition was complete the addition funnel washed with IPAc (10 mL) and then charged with isobutyl chloroformate (IBCF, 137 mmol, 19.5 mL) which was added keeping the temperature at 0±5° C. The reaction mixture was stirred at 0±5° C. for 90 min after which time a solution of cyclopropylamine (154 mmol, 10.7) in IPAc (80 mL) was added keeping the temperature at 0±5° C. Upon completion of addition the reaction was warmed to 25±5° C. and allowed to stir for 18 h. Sodium hydroxide (231 mL, 1.0 N) was added and the biphasic mixture stirred vigorously for 30 min, then the layers were separated. The organic phase was then washed with HCl (231 mL, 1.0 N). The combined organic phases were dried over sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound (19.5 g, 75%) as an orange oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[F:19])=[C:5]([O:20][CH3:21])[CH:4]=1)[CH3:2].O1CC[CH2:24][CH2:23]1>C(O)C>[CH2:23]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[O:20][CH3:21])=[C:11]([F:19])[CH:12]=1)[CH3:24]
Reactant: C1CCOC1
Reactant: CCc1ccc(Oc2ccc([N+](=O)[O-])cc2F)c(OC)c1
Solvent: CCO
Product: CCNc1ccc(Oc2ccc(CC)cc2OC)c(F)c1

Procedure:
According to the procedure of example 20 (b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for 4-ethyl-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene (1.16 g; 4.0 mmol) and tetrahydrofurane for ethanol (16 mL), two compounds were obtained after purification on silica gel (gradient cyclohexane/dichloromethane) 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (466 mg; 45%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[C:13]([CH2:18][N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Clc1cccc(I)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-chloro-3-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 486.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[S:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH:13]=2)[NH:8][C:7]=1[CH3:26])C.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>CO>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:8]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH2:16][C:17]4[S:18][C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=5[N:21]=4)=[CH:11][CH:10]=3)[C:6]([CH2:5][C:4]([OH:3])=[O:27])=[C:7]2[CH3:26])=[CH:31][CH:30]=1
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(OCc3nc4ccccc4s3)cc12
Reactant: ClCc1ccc(Cl)cc1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Cl)cc1

Procedure:
The title compound is prepared according to the method of Example 16 using 2-methyl-5-(2-benzothiazolylmethoxy)-1H-indole-3-acetic acid ethyl ester and 4chlorobenzyl chloride; however, the hydrolysis is carried out in aqueous methanol. Recrystallization from acetonitrile affords white crystals, m.p. 175°-176° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C(OCC)C>[I:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1I
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(Cl)c1ccc(F)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-iodo-4-fluorobenzoic acid (194 mg, 0.73 mmol) and phosphorus pentachloride (152 mg, 0.73 mmol) in diethyl ether (5 mL) was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to yield the 2-iodo-4-fluorobenzoyl chloride.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34][C:35]([CH3:42])=[CH:36][CH2:37][CH2:38][C:39](=O)[CH3:40]>>[CH3:40][C:39]([CH2:38][CH2:37][CH:36]=[C:35]([CH3:42])[CH3:34])=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)CCC=C(C)C
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C)=CCCC(C)=CCc1ccccc1
Yield: 17.4 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.48 g, 7.78 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.9 mL, 7.78 mmol, 1.0 equiv.) and 6-methylhept-5-en-2-one (1.48 g, 11.7 mmol, 1.5 equiv.), 0.29 g (17%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [NH2:1]C1C(Cl)=C(C=CC=1)C(N)=O.[Br:12][C:13]1[C:14]([Cl:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=1)[C:16](O)=[O:17]>>[Br:12][C:13]1[C:14]([Cl:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=1)[C:16]([NH2:1])=[O:17]
Reactant: O=C(O)c1c(F)ccc(Br)c1Cl
Reactant: NC(=O)c1cccc(N)c1Cl
Product: NC(=O)c1c(F)ccc(Br)c1Cl

Procedure:
This compound was prepared using a method analogous to that of 3-amino-2-chlorobenzamide (A.1.2), 3-bromo-2-chloro-6-fluorobenzoic acid replacing 3-amino-2-chlorobenzoic acid;
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][C:24]=2[F:26])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(F)cc1F
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2F)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 2,4-difluorobenzene boronic acid according to the general procedure B. Obtained as a yellow solid (3.26 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH:16]=[CH:15][C:14]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[Cl:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][O:19][C:17]1[CH:16]=[CH:15][C:14]([S:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[C:13]([NH:12][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: Clc1ccnc2ncccc12
Reactant: Nc1cc(OCc2cccc(Cl)c2)ccc1Sc1ccc(O)cc1
Product: Oc1ccc(Sc2ccc(OCc3cccc(Cl)c3)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (50 mg, 0.30 mmol) was reacted with the product from Example 144a (107 mg, 0.30 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (109 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3 H) 5.16 (s, 2 H) 6.25 (d, J=6.98 Hz, 1 H) 6.66 (d, J=8.83 Hz, 2 H) 7.07-7.25 (m, J=8.46 Hz, 5 H) 7.38-7.53 (m, 3 H) 7.80 (d, J=8.45 Hz, 1 H) 8.40 (d, J=6.99 Hz, 1 H) 8.99 (d, J=8.83 HZ, 1 H) 9.79 (s,1 H) 11.02 (br s,1H) 14.38 (br s,1 H); MS (ESI+) m/z 500 (M+H−TFA)+; (ESI−) m/z 498 (M−H−TFA)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](O)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([Cl:24])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)Cl
Temperature: 90 °C
Reaction time: 14 h

Procedure:
63.6 g of 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionic acid are dissolved in 700 ml of toluene, then 200 ml of toluene are removed from this solution by distillation. After cooling to 90° C., 25 ml (0.34 mole) of thionyl chloride are added dropwise and the solution is stirred for 14 hours at this temperature. The reaction mixture is then concentrated to a volume of 200 ml and the resultant solution of 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionyl chloride in toluene is used direct for the following reaction step.
Reaction SMILES: [CH3:1][C:2]([CH3:57])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:54])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:53])[CH2:21][CH2:22][C@@:23]3(/[CH:39]=[CH:40]/[C:41]([NH:43][C@H:44]([C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=4)[CH3:45])=[O:42])[CH2:35][CH2:34][C:33]([CH:36]([CH3:38])[CH3:37])=[C:24]32)[C:15]1([CH3:56])[CH3:55])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:52][C:48]1[CH:47]=[C:46]([C@@H:44]([NH:43][C:41](=[O:42])/[CH:40]=[CH:39]/[C@:23]23[CH2:35][CH2:34][C:33]([CH:36]([CH3:38])[CH3:37])=[C:24]2[C@@H:25]2[C@@:20]([CH3:53])([CH2:21][CH2:22]3)[C@@:19]3([CH3:54])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:55])([CH3:56])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:57])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH3:45])[CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2cccc(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of 1-tert-butyl 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((S)-1-(3-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (1556 mg, 1.934 mmol) in DCM (12 mL) stirred at room temp was added TFA (4 mL, 51.9 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was evaporated to dryness, then diluted with 200 ml DCM. The organic phase was washed with saturated NaHCO3 solution (200 mL*3), water and brine. The organics were dried and concentrated under reduced pressure to afford the crude product which was purified by preparative-HPLC to give the title compound (550 mg, 38%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.40-7.17 (m, 4H), 6.85 (d, J=15.3 Hz, 1H), 5.72-5.49 (m, 2H), 5.18 (t, J=7.2 Hz, 1H), 4.50 (dd, J=5.6, 10.7 Hz, 1H), 3.28-3.10 (m, 1H), 2.74-2.62 (m, 1H), 2.62-2.50 (m, 1H), 2.24 (br. s., 3H), 2.08-1.92 (m, 2H), 1.89-0.70 (m, 49H); LC/MS: m/z calculated 747.5. Found 748.2 (M+1)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[Si:20]([O:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2[nH]ncc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Yield: 97.2 %

Procedure:
A solution of 1H-indazol-5-ol (25 g, 186.38 mmol, 1.00 equiv), imidazole (31.7 g, 466.18 mmol, 2.50 equiv) and tert-butyl(chloro)dimethylsilane (33.8 g, 224.25 mmol, 1.20 equiv) in N,N-dimethylformamide (100 mL) was stirred at room temperature for 2 h. The reaction was quenched by the addition of water/ice (200 mL). The precipitate was collected by filtration and dried in a vacuum oven to give 45 g (97%) of 5-(tert-butyldimethylsilyloxy)-1H-indazole as a brown solid. 1H NMR (300 MHz, CDCl3): δ 8.00 (s, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 7.02 (dd, J=9.0 Hz, 2.4 Hz, 1H), 1.03 (s, 9H), 0.24 (s, 6H) ppm. LCMS (method D, ESI): RT=1.66 min, m/z=249.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])[CH2:3]1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:19]([NH:27][C:28]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:18])([CH3:1])[CH2:3]1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)CN(c2ccccc2N)c2ccccc21
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: CC1(C)CN(c2ccccc2NC(=S)NC(=O)c2ccccc2)c2ccccc21
Yield: 112.7 %

Procedure:
To a solution of 2e (40 mg, 0.168 mmol) in CH2Cl2 was added benzoyl isothiocyanate (30 mg, 0.189 mmol). The reaction mixture was kept at reflux for 2.5 h. The reaction mixture was filtered through a cake of Celite® and washed the cake with CH2Cl2. The solvent was evaporated under reduced pressure. The desired product was purified by column chromatography using 0 to 80% EtOAc in hexane over 60 min as eluting gradient to afford 2f (76 mg, 99%) as a powder. MS (ES) m/z 402 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:22][C:23]1([CH3:31])[C:25]([CH3:27])([CH3:26])[CH:24]1[C:28](Cl)=[O:29]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:28]([CH:24]3[C:25]([CH3:27])([CH3:26])[C:23]3([CH3:31])[CH3:22])=[O:29])=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3cc(OCc4ccccc4)ccc23)C1(C)C
Yield: 64.4 %

Procedure:
A mixture of 6-benzyloxyindole (Lancaster, 2.0 g, 9.0 mmol), ethylmagnesium bromide (1.0 M solution in THF, 11 mL, 11 mmol), zinc chloride (1.0 M solution in Et2O, 11 mL, 11 mmol) and the product of Example 1A (13.4 mmol) in 30 mL of dichloromethane was processed as described in Example 1B to provide the title compound (2.0 g, 5.8 mmol, 64% yield). MS (DCI/NH3) m/z 348 (M+H)+.